Full text data of EPHX1
EPHX1
(EPHX, EPOX)
[Confidence: high (present in two of the MS resources)]
Epoxide hydrolase 1; 3.3.2.9 (Epoxide hydratase; Microsomal epoxide hydrolase)
Epoxide hydrolase 1; 3.3.2.9 (Epoxide hydratase; Microsomal epoxide hydrolase)
UniProt
P07099
ID HYEP_HUMAN Reviewed; 455 AA.
AC P07099; B2R8N0; Q5VTJ6; Q9NP75; Q9NPE7; Q9NQU6; Q9NQU7; Q9NQU8;
read moreAC Q9NQU9; Q9NQV0; Q9NQV1; Q9NQV2;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1988, sequence version 1.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Epoxide hydrolase 1;
DE EC=3.3.2.9;
DE AltName: Full=Epoxide hydratase;
DE AltName: Full=Microsomal epoxide hydrolase;
GN Name=EPHX1; Synonyms=EPHX, EPOX;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 1-19.
RX PubMed=2891713;
RA Skoda R.C., Demierre A., McBride O.W., Gonzalez F.J., Meyer U.A.;
RT "Human microsomal xenobiotic epoxide hydrolase. Complementary DNA
RT sequence, complementary DNA-directed expression in COS-1 cells, and
RT chromosomal localization.";
RL J. Biol. Chem. 263:1549-1554(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal liver;
RA Wilson N.M., Omiecinski C.J.;
RT "Nucleotide sequence of a human microsomal epoxide hydrolase cDNA
RT clone.";
RL Submitted (JUL-1988) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=3502697; DOI=10.1093/nar/15.17.7188;
RA Jackson M.R., Craft J.A., Burchell B.;
RT "Nucleotide and deduced amino acid sequence of human liver microsomal
RT epoxide hydrolase.";
RL Nucleic Acids Res. 15:7188-7188(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS HIS-113; ARG-139 AND ILE-396.
RC TISSUE=Liver;
RX PubMed=7516776; DOI=10.1093/hmg/3.3.421;
RA Hassett C., Aicher L., Sidhu J.S., Omiecinski C.J.;
RT "Human microsomal epoxide hydrolase: genetic polymorphism and
RT functional expression in vitro of amino acid variants.";
RL Hum. Mol. Genet. 3:421-428(1994).
RN [5]
RP ERRATUM.
RA Hassett C., Aicher L., Sidhu J.S., Omiecinski C.J.;
RL Hum. Mol. Genet. 3:1214-1214(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7835893; DOI=10.1006/geno.1994.1520;
RA Hassett C., Robinson K.B., Beck N.B., Omiecinski C.J.;
RT "The human microsomal epoxide hydrolase gene (EPHX1): complete
RT nucleotide sequence and structural characterization.";
RL Genomics 23:433-442(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-43; HIS-113;
RP ARG-139; LEU-285; MET-408 AND GLN-452.
RG NIEHS SNPs program;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-327.
RC TISSUE=Liver;
RA Craft J.A., Jackson M.R., Burchell B.;
RT "Partial nucleotide sequence of a cloned cDNA for human liver
RT microsomal epoxide hydrolase.";
RL Biochem. Soc. Trans. 15:708-709(1987).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-197; 242-310 AND 348-455, AND
RP VARIANTS CYS-49; HIS-113; ARG-139; PRO-260 AND GLN-454.
RX PubMed=11058921;
RX DOI=10.1002/1098-1004(200011)16:5<450::AID-HUMU28>3.0.CO;2-1;
RA Belmahdi F., Chevalier D., Lo-Guidice J.-M., Allorge D., Cauffiez C.,
RA Lafitte J.-J., Broly F.;
RT "Identification of 6 new polymorphisms, g.11177G>A, g.14622C>T (R49C),
RT g.17540T>C, g.17639T>C, g.30929T>C, g.31074G>A (R454Q), in the human
RT microsomal epoxide hydrolase gene (EPHX1) in a French population.";
RL Hum. Mutat. 16:450-450(2000).
RN [13]
RP INVOLVEMENT IN HYPERCHOLANEMIA, AND TISSUE SPECIFICITY.
RX PubMed=12878321; DOI=10.1016/S0925-4439(03)00085-1;
RA Zhu Q.S., Xing W., Qian B., von Dippe P., Shneider B.L., Fox V.L.,
RA Levy D.;
RT "Inhibition of human m-epoxide hydrolase gene expression in a case of
RT hypercholanemia.";
RL Biochim. Biophys. Acta 1638:208-216(2003).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP VARIANTS HIS-113 AND ARG-139, AND DISEASE.
RX PubMed=12173035; DOI=10.1038/sj.ejhg.5200849;
RA Laasanen J., Romppanen E.-L., Hiltunen M., Helisalmi S., Mannermaa A.,
RA Punnonen K., Heinonen S.;
RT "Two exonic single nucleotide polymorphisms in the microsomal epoxide
RT hydrolase gene are jointly associated with preeclampsia.";
RL Eur. J. Hum. Genet. 10:569-573(2002).
RN [16]
RP VARIANT GLN-44.
RX PubMed=15618730; DOI=10.2133/dmpk.18.150;
RA Shiseki K., Itoda M., Saito Y., Nakajima Y., Maekawa K., Kimura H.,
RA Goto Y., Saitoh O., Katoh M., Ohnuma T., Kawai M., Sugai K.,
RA Ohtsuki T., Suzuki C., Minami N., Ozawa S., Sawada J.;
RT "Five novel single nucleotide polymorphisms in the EPHX1 gene encoding
RT microsomal epoxide hydrolase.";
RL Drug Metab. Pharmacokinet. 18:150-153(2003).
RN [17]
RP CHARACTERIZATION OF VARIANTS HIS-113 AND ARG-139.
RX PubMed=15535985; DOI=10.1016/j.cbi.2004.07.004;
RA Hosagrahara V.P., Rettie A.E., Hassett C., Omiecinski C.J.;
RT "Functional analysis of human microsomal epoxide hydrolase genetic
RT variants.";
RL Chem. Biol. Interact. 150:149-159(2004).
CC -!- FUNCTION: Biotransformation enzyme that catalyzes the hydrolysis
CC of arene and aliphatic epoxides to less reactive and more water
CC soluble dihydrodiols by the trans addition of water.
CC -!- CATALYTIC ACTIVITY: Cis-stilbene oxide + H(2)O = (+)-(1R,2R)-1,2-
CC diphenylethane-1,2-diol.
CC -!- SUBCELLULAR LOCATION: Microsome membrane; Single-pass type II
CC membrane protein. Endoplasmic reticulum membrane; Single-pass type
CC II membrane protein (Potential).
CC -!- TISSUE SPECIFICITY: Found in liver.
CC -!- DISEASE: Note=In some populations, the high activity haplotype
CC tyr113/his139 is overrepresented among women suffering from
CC pregnancy-induced hypertension (pre-eclampsia) when compared with
CC healthy controls.
CC -!- DISEASE: Familial hypercholanemia (FHCA) [MIM:607748]: A disorder
CC characterized by elevated serum bile acid concentrations, itching,
CC and fat malabsorption. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S33 family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ephx1/";
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DR EMBL; J03518; AAA61305.1; -; mRNA.
DR EMBL; X07936; CAA30759.1; -; mRNA.
DR EMBL; Y00424; CAA68486.1; -; mRNA.
DR EMBL; L25878; AAA52389.1; -; mRNA.
DR EMBL; L25879; AAA52390.1; -; mRNA.
DR EMBL; U06661; AAB60649.1; -; Genomic_DNA.
DR EMBL; U06656; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06657; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06658; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06659; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06660; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; AK313436; BAG36227.1; -; mRNA.
DR EMBL; AY948961; AAX81410.1; -; Genomic_DNA.
DR EMBL; AL591895; CAH71994.1; -; Genomic_DNA.
DR EMBL; BC003567; AAH03567.1; -; mRNA.
DR EMBL; BC008291; AAH08291.1; -; mRNA.
DR EMBL; BC095430; AAH95430.1; -; mRNA.
DR EMBL; M36374; AAA59580.1; -; mRNA.
DR EMBL; AF253417; AAC41694.1; -; Genomic_DNA.
DR EMBL; AF276626; AAF87726.1; -; Genomic_DNA.
DR EMBL; AF276627; AAF87727.1; -; Genomic_DNA.
DR EMBL; AF276628; AAF87728.1; -; Genomic_DNA.
DR EMBL; AF276629; AAF87729.1; -; Genomic_DNA.
DR EMBL; AF276630; AAF87730.1; -; Genomic_DNA.
DR EMBL; AF276631; AAF87731.1; -; Genomic_DNA.
DR EMBL; AF276632; AAF87732.1; -; Genomic_DNA.
DR EMBL; AF276633; AAF87733.1; -; Genomic_DNA.
DR EMBL; AF276634; AAF87734.1; -; Genomic_DNA.
DR EMBL; AF276635; AAF87735.1; -; Genomic_DNA.
DR EMBL; AF276636; AAF87736.1; -; Genomic_DNA.
DR EMBL; AF276637; AAF87737.1; -; Genomic_DNA.
DR EMBL; AF276638; AAF87738.1; -; Genomic_DNA.
DR PIR; A29939; A29939.
DR RefSeq; NP_000111.1; NM_000120.3.
DR RefSeq; NP_001129490.1; NM_001136018.2.
DR RefSeq; XP_005273142.1; XM_005273085.1.
DR UniGene; Hs.89649; -.
DR ProteinModelPortal; P07099; -.
DR SMR; P07099; 47-454.
DR IntAct; P07099; 2.
DR BindingDB; P07099; -.
DR ChEMBL; CHEMBL1968; -.
DR MEROPS; S33.971; -.
DR PhosphoSite; P07099; -.
DR DMDM; 123926; -.
DR PaxDb; P07099; -.
DR PeptideAtlas; P07099; -.
DR PRIDE; P07099; -.
DR DNASU; 2052; -.
DR Ensembl; ENST00000272167; ENSP00000272167; ENSG00000143819.
DR Ensembl; ENST00000366837; ENSP00000355802; ENSG00000143819.
DR GeneID; 2052; -.
DR KEGG; hsa:2052; -.
DR UCSC; uc001hpk.3; human.
DR CTD; 2052; -.
DR GeneCards; GC01P225997; -.
DR HGNC; HGNC:3401; EPHX1.
DR HPA; HPA020593; -.
DR MIM; 132810; gene+phenotype.
DR MIM; 607748; phenotype.
DR neXtProt; NX_P07099; -.
DR Orphanet; 238475; Familial hypercholanemia.
DR Orphanet; 1912; Fetal hydantoin syndrome.
DR PharmGKB; PA27829; -.
DR eggNOG; COG0596; -.
DR HOVERGEN; HBG002366; -.
DR InParanoid; P07099; -.
DR KO; K01253; -.
DR OMA; IYFNEVD; -.
DR SABIO-RK; P07099; -.
DR ChiTaRS; EPHX1; human.
DR GeneWiki; EPHX1; -.
DR GenomeRNAi; 2052; -.
DR NextBio; 8343; -.
DR PRO; PR:P07099; -.
DR ArrayExpress; P07099; -.
DR Bgee; P07099; -.
DR Genevestigator; P07099; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0033961; F:cis-stilbene-oxide hydrolase activity; IEA:InterPro.
DR GO; GO:0004301; F:epoxide hydrolase activity; TAS:ProtInc.
DR GO; GO:0019439; P:aromatic compound catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008152; P:metabolic process; IEA:GOC.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:UniProtKB-KW.
DR InterPro; IPR000073; AB_hydrolase_1.
DR InterPro; IPR000639; Epox_hydrolase-like.
DR InterPro; IPR010497; Epoxide_hydro_N.
DR InterPro; IPR016292; Epoxide_hydrolase.
DR Pfam; PF00561; Abhydrolase_1; 1.
DR Pfam; PF06441; EHN; 1.
DR PIRSF; PIRSF001112; Epoxide_hydrolase; 1.
DR PRINTS; PR00412; EPOXHYDRLASE.
PE 1: Evidence at protein level;
KW Aromatic hydrocarbons catabolism; Complete proteome; Detoxification;
KW Direct protein sequencing; Endoplasmic reticulum; Hydrolase; Membrane;
KW Methylation; Microsome; Polymorphism; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1 455 Epoxide hydrolase 1.
FT /FTId=PRO_0000080855.
FT TRANSMEM 2 20 Helical; Signal-anchor; (Potential).
FT MOD_RES 295 295 Omega-N-methylated arginine (By
FT similarity).
FT VARIANT 43 43 R -> T (in dbSNP:rs3738046).
FT /FTId=VAR_023303.
FT VARIANT 44 44 E -> Q.
FT /FTId=VAR_018347.
FT VARIANT 49 49 R -> C (in allele EPHX1*2;
FT dbSNP:rs2234697).
FT /FTId=VAR_013298.
FT VARIANT 113 113 Y -> H (in allele EPHX1*3; 55% of wild
FT type enzyme activity; dbSNP:rs1051740).
FT /FTId=VAR_005295.
FT VARIANT 139 139 H -> R (in allele EPHX1*4; 62% of wild
FT type enzyme activity; dbSNP:rs2234922).
FT /FTId=VAR_005296.
FT VARIANT 260 260 L -> P (in allele EPHX1*1G).
FT /FTId=VAR_013299.
FT VARIANT 275 275 T -> A (in dbSNP:rs35073925).
FT /FTId=VAR_051828.
FT VARIANT 285 285 V -> L (in dbSNP:rs45449793).
FT /FTId=VAR_023304.
FT VARIANT 396 396 T -> I (either a rare polymorphism or a
FT sequencing error).
FT /FTId=VAR_005297.
FT VARIANT 408 408 T -> M (in dbSNP:rs45495897).
FT /FTId=VAR_023305.
FT VARIANT 452 452 L -> Q (in dbSNP:rs45563137).
FT /FTId=VAR_023306.
FT VARIANT 454 454 R -> Q (in allele EPHX1*5;
FT dbSNP:rs2234701).
FT /FTId=VAR_013300.
FT CONFLICT 15 15 I -> V (in Ref. 7; BAG36227).
FT CONFLICT 112 112 R -> K (in Ref. 11).
FT CONFLICT 148 148 H -> N (in Ref. 3 and 11).
FT CONFLICT 243 243 V -> L (in Ref. 11).
FT CONFLICT 348 348 K -> S (in Ref. 3; CAA68486).
FT CONFLICT 406 406 L -> F (in Ref. 3; CAA68486).
FT CONFLICT 420 420 L -> V (in Ref. 3; CAA68486).
SQ SEQUENCE 455 AA; 52949 MW; 88E333838C841390 CRC64;
MWLEILLTSV LGFAIYWFIS RDKEETLPLE DGWWGPGTRS AAREDDSIRP FKVETSDEEI
HDLHQRIDKF RFTPPLEDSC FHYGFNSNYL KKVISYWRNE FDWKKQVEIL NRYPHFKTKI
EGLDIHFIHV KPPQLPAGHT PKPLLMVHGW PGSFYEFYKI IPLLTDPKNH GLSDEHVFEV
ICPSIPGYGF SEASSKKGFN SVATARIFYK LMLRLGFQEF YIQGGDWGSL ICTNMAQLVP
SHVKGLHLNM ALVLSNFSTL TLLLGQRFGR FLGLTERDVE LLYPVKEKVF YSLMRESGYM
HIQCTKPDTV GSALNDSPVG LAAYILEKFS TWTNTEFRYL EDGGLERKFS LDDLLTNVML
YWTTGTIISS QRFYKENLGQ GWMTQKHERM KVYVPTGFSA FPFELLHTPE KWVRFKYPKL
ISYSYMVRGG HFAAFEEPEL LAQDIRKFLS VLERQ
//
ID HYEP_HUMAN Reviewed; 455 AA.
AC P07099; B2R8N0; Q5VTJ6; Q9NP75; Q9NPE7; Q9NQU6; Q9NQU7; Q9NQU8;
read moreAC Q9NQU9; Q9NQV0; Q9NQV1; Q9NQV2;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1988, sequence version 1.
DT 22-JAN-2014, entry version 148.
DE RecName: Full=Epoxide hydrolase 1;
DE EC=3.3.2.9;
DE AltName: Full=Epoxide hydratase;
DE AltName: Full=Microsomal epoxide hydrolase;
GN Name=EPHX1; Synonyms=EPHX, EPOX;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 1-19.
RX PubMed=2891713;
RA Skoda R.C., Demierre A., McBride O.W., Gonzalez F.J., Meyer U.A.;
RT "Human microsomal xenobiotic epoxide hydrolase. Complementary DNA
RT sequence, complementary DNA-directed expression in COS-1 cells, and
RT chromosomal localization.";
RL J. Biol. Chem. 263:1549-1554(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal liver;
RA Wilson N.M., Omiecinski C.J.;
RT "Nucleotide sequence of a human microsomal epoxide hydrolase cDNA
RT clone.";
RL Submitted (JUL-1988) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=3502697; DOI=10.1093/nar/15.17.7188;
RA Jackson M.R., Craft J.A., Burchell B.;
RT "Nucleotide and deduced amino acid sequence of human liver microsomal
RT epoxide hydrolase.";
RL Nucleic Acids Res. 15:7188-7188(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS HIS-113; ARG-139 AND ILE-396.
RC TISSUE=Liver;
RX PubMed=7516776; DOI=10.1093/hmg/3.3.421;
RA Hassett C., Aicher L., Sidhu J.S., Omiecinski C.J.;
RT "Human microsomal epoxide hydrolase: genetic polymorphism and
RT functional expression in vitro of amino acid variants.";
RL Hum. Mol. Genet. 3:421-428(1994).
RN [5]
RP ERRATUM.
RA Hassett C., Aicher L., Sidhu J.S., Omiecinski C.J.;
RL Hum. Mol. Genet. 3:1214-1214(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7835893; DOI=10.1006/geno.1994.1520;
RA Hassett C., Robinson K.B., Beck N.B., Omiecinski C.J.;
RT "The human microsomal epoxide hydrolase gene (EPHX1): complete
RT nucleotide sequence and structural characterization.";
RL Genomics 23:433-442(1994).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-43; HIS-113;
RP ARG-139; LEU-285; MET-408 AND GLN-452.
RG NIEHS SNPs program;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, Testis, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-327.
RC TISSUE=Liver;
RA Craft J.A., Jackson M.R., Burchell B.;
RT "Partial nucleotide sequence of a cloned cDNA for human liver
RT microsomal epoxide hydrolase.";
RL Biochem. Soc. Trans. 15:708-709(1987).
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-197; 242-310 AND 348-455, AND
RP VARIANTS CYS-49; HIS-113; ARG-139; PRO-260 AND GLN-454.
RX PubMed=11058921;
RX DOI=10.1002/1098-1004(200011)16:5<450::AID-HUMU28>3.0.CO;2-1;
RA Belmahdi F., Chevalier D., Lo-Guidice J.-M., Allorge D., Cauffiez C.,
RA Lafitte J.-J., Broly F.;
RT "Identification of 6 new polymorphisms, g.11177G>A, g.14622C>T (R49C),
RT g.17540T>C, g.17639T>C, g.30929T>C, g.31074G>A (R454Q), in the human
RT microsomal epoxide hydrolase gene (EPHX1) in a French population.";
RL Hum. Mutat. 16:450-450(2000).
RN [13]
RP INVOLVEMENT IN HYPERCHOLANEMIA, AND TISSUE SPECIFICITY.
RX PubMed=12878321; DOI=10.1016/S0925-4439(03)00085-1;
RA Zhu Q.S., Xing W., Qian B., von Dippe P., Shneider B.L., Fox V.L.,
RA Levy D.;
RT "Inhibition of human m-epoxide hydrolase gene expression in a case of
RT hypercholanemia.";
RL Biochim. Biophys. Acta 1638:208-216(2003).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP VARIANTS HIS-113 AND ARG-139, AND DISEASE.
RX PubMed=12173035; DOI=10.1038/sj.ejhg.5200849;
RA Laasanen J., Romppanen E.-L., Hiltunen M., Helisalmi S., Mannermaa A.,
RA Punnonen K., Heinonen S.;
RT "Two exonic single nucleotide polymorphisms in the microsomal epoxide
RT hydrolase gene are jointly associated with preeclampsia.";
RL Eur. J. Hum. Genet. 10:569-573(2002).
RN [16]
RP VARIANT GLN-44.
RX PubMed=15618730; DOI=10.2133/dmpk.18.150;
RA Shiseki K., Itoda M., Saito Y., Nakajima Y., Maekawa K., Kimura H.,
RA Goto Y., Saitoh O., Katoh M., Ohnuma T., Kawai M., Sugai K.,
RA Ohtsuki T., Suzuki C., Minami N., Ozawa S., Sawada J.;
RT "Five novel single nucleotide polymorphisms in the EPHX1 gene encoding
RT microsomal epoxide hydrolase.";
RL Drug Metab. Pharmacokinet. 18:150-153(2003).
RN [17]
RP CHARACTERIZATION OF VARIANTS HIS-113 AND ARG-139.
RX PubMed=15535985; DOI=10.1016/j.cbi.2004.07.004;
RA Hosagrahara V.P., Rettie A.E., Hassett C., Omiecinski C.J.;
RT "Functional analysis of human microsomal epoxide hydrolase genetic
RT variants.";
RL Chem. Biol. Interact. 150:149-159(2004).
CC -!- FUNCTION: Biotransformation enzyme that catalyzes the hydrolysis
CC of arene and aliphatic epoxides to less reactive and more water
CC soluble dihydrodiols by the trans addition of water.
CC -!- CATALYTIC ACTIVITY: Cis-stilbene oxide + H(2)O = (+)-(1R,2R)-1,2-
CC diphenylethane-1,2-diol.
CC -!- SUBCELLULAR LOCATION: Microsome membrane; Single-pass type II
CC membrane protein. Endoplasmic reticulum membrane; Single-pass type
CC II membrane protein (Potential).
CC -!- TISSUE SPECIFICITY: Found in liver.
CC -!- DISEASE: Note=In some populations, the high activity haplotype
CC tyr113/his139 is overrepresented among women suffering from
CC pregnancy-induced hypertension (pre-eclampsia) when compared with
CC healthy controls.
CC -!- DISEASE: Familial hypercholanemia (FHCA) [MIM:607748]: A disorder
CC characterized by elevated serum bile acid concentrations, itching,
CC and fat malabsorption. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S33 family.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/ephx1/";
CC -----------------------------------------------------------------------
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DR EMBL; J03518; AAA61305.1; -; mRNA.
DR EMBL; X07936; CAA30759.1; -; mRNA.
DR EMBL; Y00424; CAA68486.1; -; mRNA.
DR EMBL; L25878; AAA52389.1; -; mRNA.
DR EMBL; L25879; AAA52390.1; -; mRNA.
DR EMBL; U06661; AAB60649.1; -; Genomic_DNA.
DR EMBL; U06656; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06657; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06658; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06659; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; U06660; AAB60649.1; JOINED; Genomic_DNA.
DR EMBL; AK313436; BAG36227.1; -; mRNA.
DR EMBL; AY948961; AAX81410.1; -; Genomic_DNA.
DR EMBL; AL591895; CAH71994.1; -; Genomic_DNA.
DR EMBL; BC003567; AAH03567.1; -; mRNA.
DR EMBL; BC008291; AAH08291.1; -; mRNA.
DR EMBL; BC095430; AAH95430.1; -; mRNA.
DR EMBL; M36374; AAA59580.1; -; mRNA.
DR EMBL; AF253417; AAC41694.1; -; Genomic_DNA.
DR EMBL; AF276626; AAF87726.1; -; Genomic_DNA.
DR EMBL; AF276627; AAF87727.1; -; Genomic_DNA.
DR EMBL; AF276628; AAF87728.1; -; Genomic_DNA.
DR EMBL; AF276629; AAF87729.1; -; Genomic_DNA.
DR EMBL; AF276630; AAF87730.1; -; Genomic_DNA.
DR EMBL; AF276631; AAF87731.1; -; Genomic_DNA.
DR EMBL; AF276632; AAF87732.1; -; Genomic_DNA.
DR EMBL; AF276633; AAF87733.1; -; Genomic_DNA.
DR EMBL; AF276634; AAF87734.1; -; Genomic_DNA.
DR EMBL; AF276635; AAF87735.1; -; Genomic_DNA.
DR EMBL; AF276636; AAF87736.1; -; Genomic_DNA.
DR EMBL; AF276637; AAF87737.1; -; Genomic_DNA.
DR EMBL; AF276638; AAF87738.1; -; Genomic_DNA.
DR PIR; A29939; A29939.
DR RefSeq; NP_000111.1; NM_000120.3.
DR RefSeq; NP_001129490.1; NM_001136018.2.
DR RefSeq; XP_005273142.1; XM_005273085.1.
DR UniGene; Hs.89649; -.
DR ProteinModelPortal; P07099; -.
DR SMR; P07099; 47-454.
DR IntAct; P07099; 2.
DR BindingDB; P07099; -.
DR ChEMBL; CHEMBL1968; -.
DR MEROPS; S33.971; -.
DR PhosphoSite; P07099; -.
DR DMDM; 123926; -.
DR PaxDb; P07099; -.
DR PeptideAtlas; P07099; -.
DR PRIDE; P07099; -.
DR DNASU; 2052; -.
DR Ensembl; ENST00000272167; ENSP00000272167; ENSG00000143819.
DR Ensembl; ENST00000366837; ENSP00000355802; ENSG00000143819.
DR GeneID; 2052; -.
DR KEGG; hsa:2052; -.
DR UCSC; uc001hpk.3; human.
DR CTD; 2052; -.
DR GeneCards; GC01P225997; -.
DR HGNC; HGNC:3401; EPHX1.
DR HPA; HPA020593; -.
DR MIM; 132810; gene+phenotype.
DR MIM; 607748; phenotype.
DR neXtProt; NX_P07099; -.
DR Orphanet; 238475; Familial hypercholanemia.
DR Orphanet; 1912; Fetal hydantoin syndrome.
DR PharmGKB; PA27829; -.
DR eggNOG; COG0596; -.
DR HOVERGEN; HBG002366; -.
DR InParanoid; P07099; -.
DR KO; K01253; -.
DR OMA; IYFNEVD; -.
DR SABIO-RK; P07099; -.
DR ChiTaRS; EPHX1; human.
DR GeneWiki; EPHX1; -.
DR GenomeRNAi; 2052; -.
DR NextBio; 8343; -.
DR PRO; PR:P07099; -.
DR ArrayExpress; P07099; -.
DR Bgee; P07099; -.
DR Genevestigator; P07099; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0033961; F:cis-stilbene-oxide hydrolase activity; IEA:InterPro.
DR GO; GO:0004301; F:epoxide hydrolase activity; TAS:ProtInc.
DR GO; GO:0019439; P:aromatic compound catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008152; P:metabolic process; IEA:GOC.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:UniProtKB-KW.
DR InterPro; IPR000073; AB_hydrolase_1.
DR InterPro; IPR000639; Epox_hydrolase-like.
DR InterPro; IPR010497; Epoxide_hydro_N.
DR InterPro; IPR016292; Epoxide_hydrolase.
DR Pfam; PF00561; Abhydrolase_1; 1.
DR Pfam; PF06441; EHN; 1.
DR PIRSF; PIRSF001112; Epoxide_hydrolase; 1.
DR PRINTS; PR00412; EPOXHYDRLASE.
PE 1: Evidence at protein level;
KW Aromatic hydrocarbons catabolism; Complete proteome; Detoxification;
KW Direct protein sequencing; Endoplasmic reticulum; Hydrolase; Membrane;
KW Methylation; Microsome; Polymorphism; Reference proteome;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1 455 Epoxide hydrolase 1.
FT /FTId=PRO_0000080855.
FT TRANSMEM 2 20 Helical; Signal-anchor; (Potential).
FT MOD_RES 295 295 Omega-N-methylated arginine (By
FT similarity).
FT VARIANT 43 43 R -> T (in dbSNP:rs3738046).
FT /FTId=VAR_023303.
FT VARIANT 44 44 E -> Q.
FT /FTId=VAR_018347.
FT VARIANT 49 49 R -> C (in allele EPHX1*2;
FT dbSNP:rs2234697).
FT /FTId=VAR_013298.
FT VARIANT 113 113 Y -> H (in allele EPHX1*3; 55% of wild
FT type enzyme activity; dbSNP:rs1051740).
FT /FTId=VAR_005295.
FT VARIANT 139 139 H -> R (in allele EPHX1*4; 62% of wild
FT type enzyme activity; dbSNP:rs2234922).
FT /FTId=VAR_005296.
FT VARIANT 260 260 L -> P (in allele EPHX1*1G).
FT /FTId=VAR_013299.
FT VARIANT 275 275 T -> A (in dbSNP:rs35073925).
FT /FTId=VAR_051828.
FT VARIANT 285 285 V -> L (in dbSNP:rs45449793).
FT /FTId=VAR_023304.
FT VARIANT 396 396 T -> I (either a rare polymorphism or a
FT sequencing error).
FT /FTId=VAR_005297.
FT VARIANT 408 408 T -> M (in dbSNP:rs45495897).
FT /FTId=VAR_023305.
FT VARIANT 452 452 L -> Q (in dbSNP:rs45563137).
FT /FTId=VAR_023306.
FT VARIANT 454 454 R -> Q (in allele EPHX1*5;
FT dbSNP:rs2234701).
FT /FTId=VAR_013300.
FT CONFLICT 15 15 I -> V (in Ref. 7; BAG36227).
FT CONFLICT 112 112 R -> K (in Ref. 11).
FT CONFLICT 148 148 H -> N (in Ref. 3 and 11).
FT CONFLICT 243 243 V -> L (in Ref. 11).
FT CONFLICT 348 348 K -> S (in Ref. 3; CAA68486).
FT CONFLICT 406 406 L -> F (in Ref. 3; CAA68486).
FT CONFLICT 420 420 L -> V (in Ref. 3; CAA68486).
SQ SEQUENCE 455 AA; 52949 MW; 88E333838C841390 CRC64;
MWLEILLTSV LGFAIYWFIS RDKEETLPLE DGWWGPGTRS AAREDDSIRP FKVETSDEEI
HDLHQRIDKF RFTPPLEDSC FHYGFNSNYL KKVISYWRNE FDWKKQVEIL NRYPHFKTKI
EGLDIHFIHV KPPQLPAGHT PKPLLMVHGW PGSFYEFYKI IPLLTDPKNH GLSDEHVFEV
ICPSIPGYGF SEASSKKGFN SVATARIFYK LMLRLGFQEF YIQGGDWGSL ICTNMAQLVP
SHVKGLHLNM ALVLSNFSTL TLLLGQRFGR FLGLTERDVE LLYPVKEKVF YSLMRESGYM
HIQCTKPDTV GSALNDSPVG LAAYILEKFS TWTNTEFRYL EDGGLERKFS LDDLLTNVML
YWTTGTIISS QRFYKENLGQ GWMTQKHERM KVYVPTGFSA FPFELLHTPE KWVRFKYPKL
ISYSYMVRGG HFAAFEEPEL LAQDIRKFLS VLERQ
//
MIM
132810
*RECORD*
*FIELD* NO
132810
*FIELD* TI
+132810 EPOXIDE HYDROLASE 1, MICROSOMAL; EPHX1
;;EPOXIDE HYDROLASE; EPHX;;
EPOXIDE HYDROLASE, MICROSOMAL XENOBIOTIC; EPOX
read morePHENYTOIN TOXICITY, INCLUDED;;
ARENE OXIDE DETOXIFICATION DEFECT, INCLUDED;;
FETAL HYDANTOIN SYNDROME, INCLUDED; FHS, INCLUDED;;
DIPHENYLHYDANTOIN, DEFECT IN HYDROXYLATION OF, INCLUDED;;
LYMPHOPROLIFERATIVE DISORDERS, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
DESCRIPTION
Epoxide hydrolases (EC 3.3.2.3) play an important role in both the
activation and detoxification of exogenous chemicals such as polycyclic
aromatic hydrocarbons.
CLONING
Jackson et al. (1987) reported the nucleotide sequence of EPOX. The
deduced protein is 455 residues long and 82% homologous to rat
microsomal epoxide hydrolase.
Skoda et al. (1988) isolated cDNA clones for human microsomal epoxide
hydrolase and determined the nucleotide sequence. The deduced amino acid
sequence of the human enzyme was found to be 80% similar to the
previously reported rabbit enzyme and 84% similar to the deduced rat
protein sequence. The N-terminal amino acids deduced from the human cDNA
were identical to the published 19 N-terminal amino acids of the
purified human enzyme. Northern blot analysis showed a single mRNA band
of 1.8 kilobases. Southern blot analysis indicated that there is only 1
copy of the gene per haploid genome. Several restriction fragment length
polymorphisms were observed with the human EPOX cDNA.
Hassett et al. (1994) isolated and sequenced clones that encoded the
entire human EPHX1 gene. The primary nuclear transcript, extending from
the start of transcription to the site of poly(A) addition, is 20,271
nucleotides long.
GENE STRUCTURE
Hassett et al. (1994) determined that the EPHX1 gene contains 9 exons
separated by 8 introns; canonical intron/exon boundary sites were
observed at each junction. The introns vary in size from 335 to 6,696
basepairs and contain numerous repetitive DNA elements, including 18 Alu
sequences (each more than 100 nucleotides long) within 4 of the introns.
MAPPING
Brown and Chalmers (1986) measured microsomal epoxide hydrolase activity
in human/mouse hybrid cells prepared from human cells expressing 6 to 7
times the activity of the mouse cells. Of 25 clones examined by
antihuman and antimouse antisera raised in the rabbit, none expressed
human enzyme. This correlated with the loss of human chromosome 6 from
each cell line. Brown and Chalmers (1986) concluded that the human gene
for epoxide hydrolase may be on chromosome 6. Certain observations in
hybrid cells suggested that other gene products can affect the level of
activity expressed by the cell. Brown and Chalmers (1986) recognized
that assignment of genes to chromosomes on the basis of negative data is
not completely satisfactory. They also observed that other chromosomes,
particularly chromosome 19, seemed to affect expression. Jackson et al.
(1987) assigned the gene to chromosome 1 by somatic cell hybridization.
Analysis of 2 hybrids containing spontaneous breaks permitted regional
localization of the gene to 1q or proximal to NRAS (164790) on 1p. By
fluorescence in situ hybridization, Hartsfield et al. (1998) mapped the
EPOX gene to 1q42.1 The mouse equivalent of EPOX, symbolized Eph-1, is
located on chromosome 1 (Nadeau, 1988).
PHENOTYPE
Strickler et al. (1985) hypothesized a mutant form of microsomal epoxide
hydrolase as the molecular basis for abnormal reactions to phenytoin and
some other drugs. Phenytoin (diphenylhydantoin, dilantin) is metabolized
by cytochrome P-450 monooxygenases to several oxidized products,
including parahydroxylated and dihydrodiol metabolites (see 124020).
Arene oxides, which are reactive electrophilic compounds, are
intermediates in these oxidative reactions. If not detoxified, arene
oxide metabolites can covalently bind to cell macromolecules, resulting
in cell death, mutation, tumors, birth defects, and, by acting as
haptens, can lead to secondary immune phenomena. In animals, toxic
effects of phenytoin, including gingival hyperplasia and teratogenicity,
have been attributed to the arene oxide metabolites.
Spielberg et al. (1981) studied individual susceptibility to toxicity
from phenytoin metabolites by exposing human lymphocytes to metabolites
generated by a murine hepatic microsomal system. Cells from 17 controls
showed no toxicity at concentrations of phenytoin from 31 to 125
micromoles. Cells from 3 patients with phenytoin hepatotoxicity
manifested dose-dependent toxicity from the metabolites. Phenytoin alone
was not toxic to cells. The patients' dose-response curves resembled the
response of control cells in which epoxide hydrolase, a detoxification
enzyme for arene oxides, was inhibited. Detoxification of non-arene
oxide metabolites (e.g., of acetaminophen) was normal in patients'
cells. Cells from parents of 2 patients had intermediate responses.
Cells from a sib of 1 patient showed no toxicity. A sib of another
patient had a response similar to that of the patient. The fetal
hydantoin syndrome has been observed in multiple sibs (e.g., Hanson et
al., 1976).
Phelan et al. (1981) observed dizygotic twins in whom the evidence of
diandric origin through superfecundation was strong (about 150 to 1).
One suspected father was black, the other white. Throughout pregnancy
the mother had taken phenobarbital and dilantin. Only 1 of the twins had
signs of the fetal hydantoin syndrome.
Strickler et al. (1985) presented evidence that they felt supported a
genetic predisposition to phenytoin-induced birth defects. Lymphocytes
from 24 children exposed to phenytoin throughout gestation and from
their families were challenged with phenytoin metabolites generated by a
mouse hepatic microsomal drug-metabolizing system. Fourteen of the
children had a positive assay result, i.e., a significant increase in
cell death associated with phenytoin metabolites. Each of these 14
children had 1 parent whose cells were also positive. A positive in
vitro challenge was highly correlated with major birth defects including
congenital heart disease, cleft lip/palate, microcephaly, and major
genitourinary, eye, and limb defects. There was no difference between
children with positive and negative results in the number or
distribution of minor birth defects and even features that have been
thought to be pathognomonic of the fetal hydantoin syndrome, such as
distal digital hypoplasia, were distributed evenly among children with
positive and negative assays. Some have questioned whether the epilepsy
rather than the drug used in its treatment is responsible for the
clinical abnormalities observed in the children of epileptic women
treated with hydantoin.
Chodirker et al. (1987) presented instructive observations of the
hydantoin effect in a child born of a nonepileptic mother who had been
given the drug during pregnancy for seizure prophylaxis after brain
surgery. Goldman et al. (1987) found that children with the fetal
hydantoin syndrome (FHS) had glucocorticoid receptor (138040) levels in
circulating lymphocytes significantly higher than those of unaffected
children with similar exposure to phenytoin. The receptor level of
affected children was also significantly elevated above that of fathers
of children with FHS and of fathers and mothers of control children. The
authors suggested that elevated levels of glucocorticoid receptors and
lymphocytes may be a marker for susceptibility to FHS.
Diphenylhydantoin is poorly excreted by the kidney. Removal from the
body depends on its hydroxylation. Kutt et al. (1964) found a family in
which 3 members had reduced ability to hydroxylate diphenylhydantoin.
The proband, who developed toxicity on usual doses of the drug, showed
accumulation of the drug and much less hydroxylated derivative than
normal in the urine. A defect in the hydroxylation of diphenylhydantoin
can be produced by simultaneous administration of isoniazid (INH) which
inhibits hydroxylation by liver microsomes (Kutt et al., 1968). Patients
who show intolerance to diphenylhydantoin when receiving INH at the same
time are patients who are the slow acetylators (243400) of INH (Kutt et
al., 1970; Brennan et al., 1970). The family reported by Kutt et al.
(1964) had a mother and 2 sons with inadequate hydroxylation. The
proband was one of the sons, a 24-year-old male without liver disease,
who consulted the authors 3 weeks after he had been given a daily dosage
of 300 mg diphenylhydantoin and 90 mg phenobarbital for control of
seizures after head injury. He showed marked nystagmus, ataxia and
mental blunting, which disappeared when diphenylhydantoin was
discontinued and reappeared when it was given again. Barbiturates alone
produce no toxicity. Vasko et al. (1977) also reported a family. The
proband was a 32-year-old epileptic who developed high blood levels and
toxicity on a moderate dose. The 24-hour urinary output of
5-(p-hydroxyphenyl)-5-phenylhydantoin was only 50% of the ingested drug.
The half-life of the drug was 32 hours. At least one child had a
prolonged half-life. Dominant inheritance was proposed by Vesell (1979).
Vasko et al. (1980) observed phenytoin hypometabolism in 4 members of 4
generations of a kindred. Presumably the defect in hydroxylation of
diphenylhydantoin (also known as phenytoin) is unrelated to the
mephenytoin-metabolizing P450 system (124020) (Spielberg, 1988).
Vermeij et al. (1988) studied the inheritance of deficient phenytoin
p-hydroxylation in the family of a patient who had previously suffered
from phenytoin intoxication caused by insufficient metabolism of this
drug (de Wolff et al., 1983). The rate of phenytoin metabolism was
derived from the phenytoin/metabolite ratio in serum 6 hours after an
oral test dose of 300 mg phenytoin. The propositus, a brother, and a
sister were very slow metabolizers of phenytoin, with a metabolic ratio
of approximately 20. All 22 children of these 3 individuals showed a
mean metabolic ratio of 6.6 (SD = 1.7), whereas a control group of 37
individuals showed a mean metabolic ratio of 3.7 (SD = 1.8).
Buehler et al. (1990) appeared to have demonstrated that low epoxide
hydrolase activity in amniocytes is a risk factor for congenital
malformations in the infants of mothers receiving phenytoin. In a random
sample of amniocytes from 100 pregnant women, thin-layer chromatography
showed an apparently trimodal distribution, suggesting that the level of
the enzyme was controlled by a single gene with 2 allelic forms. In a
prospective study of 19 pregnancies monitored by amniocentesis, an
adverse outcome was predicted for 4 fetuses on the basis of low enzyme
activity (less than 30% of the standard). In all 4 cases, the mother was
receiving phenytoin monotherapy, and, after birth, the infants had
clinical findings compatible with the fetal hydantoin syndrome. The 15
fetuses with enzyme activity above 30% of the standard were not
considered to be at risk, and all 15 neonates lacked any characteristics
of the fetal hydantoin syndrome.
Gennis et al. (1991) described 3 sibs out of 12 who developed
hypersensitivity reactions to phenytoin characterized by fever, rash,
lymphadenopathy, and anicteric hepatitis. All recovered completely after
discontinuation of treatment. One sib tolerated phenobarbital without
toxic sequelae. Peripheral blood monocytes from the 3 patients and from
5 additional sibs who had never taken anticonvulsants were exposed to
oxidative metabolites of phenytoin, phenobarbital, and carbamazepine.
The cells from each of the 3 patients demonstrated increased toxicity
from metabolites of phenytoin and carbamazepine, while the cellular
response to metabolites of phenobarbital was within normal limits. Cells
from 4 of the 5 other sibs showed an abnormal response to phenytoin
metabolites, while cells from the fifth sib detoxified phenytoin
metabolites normally.
Sabry and Farag (1996) suggested that hand anomaly in the fetal
hydantoin syndrome can be unilateral acheiria at one extreme with
nail/phalangeal hypoplasia at the other extreme. They reported the case
of a baby born with absence of the right hand with rudimentary tags at
the distal end of the right forearm. The infant was born of a
nonepileptic mother who had a history of first trimester prophylactic
anticonvulsant therapy after surgical excision of a meningioma. The
status of the nails and phalanges in the left hand was not stated.
De Smet and Debeer (2002) described 2 children whose mother had been
treated with phenylhydantoin for epilepsy that developed after surgery
for a brain tumor. The first son had hypoplasia of the terminal phalanx
of the fifth finger of the left hand. The second son was born with
severe malformation of the right hand consistent with vascular
disruption. He had facial dysmorphism with ocular hypertelorism, a small
triangular shaped skull, and a depressed nasal bridge.
MOLECULAR GENETICS
Microsomal epoxide hydrolase is a bifunctional protein that plays a
central role not only in carcinogen metabolism but is also able to
mediate the sodium-dependent uptake of bile acids into hepatocytes. Zhu
et al. (2003) studied a patient with extremely elevated serum bile salt
levels (hypercholanemia; 607748) in the absence of observable
hepatocellular injury, suggesting a defect in bile acid uptake. In this
individual, EPHX1 protein and mRNA levels were reduced by approximately
95% and 85%, respectively, whereas the expression and amino acid
sequence of another bile acid transport protein, sodium/taurocholate
cotransporting polypeptide (NTCP1; 182396), was unaffected. Sequence
analysis of the EPHX1 gene identified 2 point mutations, a -4238T-A
transversion in an upstream HNF3 site in 1 allele (132180.0003) and a
2557C-G transversion in intron 1 in the other allele (132180.0004),
which resulted in a significant decrease in EPHX1 promoter activity in
transient transfection assays.
ANIMAL MODEL
Miyata et al. (1999) determined that Ephx1-null mice were fertile and
had no phenotypic abnormalities. Ephx1-null embryonic fibroblasts were
unable to produce the carcinogenic metabolite of
7,12-dimethylbenz(alpha)anthracene (DMBA), an experimental prototype for
the polycyclic aromatic hydrocarbon class of chemical carcinogens. These
mice were resistant to DMBA-mediated toxicity and DMBA-induced
carcinogenesis.
*FIELD* AV
.0001
LYMPHOPROLIFERATIVE DISORDERS, SUSCEPTIBILITY TO
PREECLAMPSIA, SUSCEPTIBILITY TO, INCLUDED;;
EMPHYSEMA, SUSCEPTIBILITY TO, INCLUDED;;
PULMONARY DISEASE, CHRONIC OBSTRUCTIVE, SUSCEPTIBILITY TO, INCLUDED
EPHX1, TYR113HIS
Hassett et al. (1994) described a correlation between mutant alleles of
EPHX and diminished enzymatic activity. They demonstrated by in vitro
expression studies of cDNA that substitution of his113 for the more
commonly occurring tyr113 residue in exon 3 decreased EPHX activity
approximately 40%. Variation of this type may be responsible for genetic
susceptibility to the environmental carcinogen aflatoxin B1 (McGlynn et
al., 1995), and explained variation in the frequency of hepatocellular
carcinoma (HCC; 114550).
Lymphoproliferative Disorder Susceptibility
Sarmanova et al. (2001) determined the frequency of polymorphisms in
several biotransformation enzymes in patients with morbus Hodgkin and
non-Hodgkin lymphomas (NHL; 605027) and age- and sex-matched healthy
individuals. The distribution of genotypes in CYP2E1-intron 6
(124040.0002) was significantly different between the control group and
all lymphomas (P = 0.03), patients with NHL (P = 0.024), and especially
aggressive diffuse NHL (P = 0.007). The EPHX-exon 3 genotype
distribution was significantly different between control males and males
with all lymphomas (P = 0.01) or with NHL (P = 0.019). The authors
suggested that genetic polymorphisms of biotransformation enzymes may
play a significant role in the development of lymphoid malignancies.
Preeclampsia Susceptibility
Zusterzeel et al. (2001) studied genetic variability of the EPHX1 gene
in women with a history of preeclampsia (189800). They found a
significantly higher frequency of the high activity tyr113/tyr113
genotype (odds ratio 2.0, 95% C.I. 1.2-3.7) in women with a history of
preeclampsia compared to controls.
Chronic Obstructive Pulmonary Disease (COPD) and Emphysema
Susceptibility
Smith and Harrison (1997) studied EPHX1 polymorphisms in patients with
various pulmonary diseases and found that the very slow phenotype
(his113) was 4 to 5 times more common in patients with COPD or emphysema
compared to controls.
.0002
EPOXIDE HYDROLASE POLYMORPHISM
EPHX1, HIS139ARG
Laasanen et al. (2002) studied an A-G polymorphism (his139 to arg) in
exon 4 of the EPHX1 gene in 133 Finnish preeclamptic and 115 healthy
control women with at least 2 normal pregnancies. Genotype and allele
distributions did not reveal statistically significant single-point
association with preeclampsia (189800). However, haplotype analysis
using this polymorphism and the exon 3 T-C polymorphism (tyr113 to his;
132810.0001) showed that the high activity haplotype T/A (tyr113/his139)
was significantly overrepresented in the preeclampsia group (P = 0.01;
odds ratio 1.61, 95% C.I. 1.12-2.32).
.0003
HYPERCHOLANEMIA, FAMILIAL
EPHX1, -4238T-A
In a patient with hypercholanemia (607748) in the absence of observable
hepatocellular injury, suggesting a defect in bile acid uptake, Zhu et
al. (2003) identified compound heterozygosity for mutations in the EPHX1
gene: one allele had a -4238T-A transversion in the 5-prime region at a
putative HNF3 site inherited from the father, and the other had a
2557C-G transversion in intron 1 (132810.0004). Both mutations
significantly decreased EPHX1 promoter activity. EPHX1 protein and mRNA
levels were reduced by approximately 95% and 85%, respectively. The
existence of both mutant alleles appeared to be necessary for the
observed hypercholanemia, since the father, who possessed only the
-4238T-A transversion, had normal serum glycocholate levels.
.0004
HYPERCHOLANEMIA, FAMILIAL
EPHX1, 2557C-G
See 132810.0003 and Zhu et al. (2003).
*FIELD* RF
1. Brennan, R. W.; Dehejia, H.; Kutt, H.; Verebely, K.; McDowell,
F.: Diphenylhydantoin intoxication attendant to slow inactivation
of isoniazid. Neurology 20: 687-693, 1970.
2. Brown, S.; Chalmers, D. E.: Microsomal epoxide hydrolase activity
in human x mouse hybrid cells. Biochem. Biophys. Res. Commun. 137:
775-780, 1986.
3. Buehler, B. A.; Delimont, D.; van Waes, M.; Finnell, R. H.: Prenatal
prediction of risk of the fetal hydantoin syndrome. New Eng. J. Med. 322:
1567-1571, 1990.
4. Chodirker, B. N.; Chudley, A. E.; Reed, M. H.; Persaud, T. V. N.
: Possible prenatal hydantoin effect in a child born to a nonepileptic
mother. Am. J. Med. Genet. 27: 373-378, 1987.
5. De Smet, L.; Debeer, P.: Fetal hydantoin syndrome with unilateral
atypical cleft hand: additional evidence for vascular disruption. Genet.
Counsel. 13: 157-161, 2002.
6. de Wolff, F. A.; Vermeij, P.; Ferrari, M. D.; Buruma, O. J. S.;
Breimer, D. D.: Impairment of phenytoin parahydroxylation as a cause
of severe intoxication. Ther. Drug Monit. 5: 213-215, 1983.
7. Gennis, M. A.; Vemuri, R.; Burns, E. A.; Hill, J. V.; Miller, M.
A.; Spielberg, S. P.: Familial occurrence of hypersensitivity to
phenytoin. Am. J. Med. 91: 631-634, 1991.
8. Goldman, A. S.; Van Dyke, D. C.; Gupta, C.; Katsumata, M.: Elevated
glucocorticoid receptor levels in lymphocytes of children with the
fetal hydantoin syndrome (FHS). Am. J. Med. Genet. 28: 607-618,
1987.
9. Hanson, J. W.; Myrianthopoulos, N. C.; Sedgwick, M. H. A.; Smith,
D. W.: Risks to the offspring of women treated with hydantoin anticonvulsants,
with emphasis on the fetal hydantoin syndrome. J. Pediat. 89: 662-668,
1976.
10. Hartsfield, J. K., Jr.; Sutcliffe, M. J.; Everett, E. T.; Hassett,
C.; Omiecinski, C. J.; Saari, J. A.: Assignment of microsomal epoxide
hydrolase (EPHX1) to human chromosome 1q42.1 by in situ hybridization. Cytogenet.
Cell Genet. 83: 44-45, 1998.
11. Hassett, C.; Aicher, L.; Sidhu, J. S.; Omiecinski, C. J.: Human
microsomal epoxide hydrolase: genetic polymorphism and functional
expression in vitro of amino acid variants. Hum. Molec. Genet. 3:
421-428, 1994. Note: Erratum: Hum. Molec. Genet. 3: 1214 only, 1994.
12. Hassett, C.; Robinson, K. B.; Beck, N. B.; Omiecinski, C. J.:
The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide
sequence and structural characterization. Genomics 23: 433-442,
1994.
13. Jackson, M. R.; Craft, J. A.; Burchell, B.: Nucleotide and deduced
amino acid sequence of human liver microsomal epoxide hydrolase. Nucleic
Acids Res. 15: 7188 only, 1987.
14. Kutt, H.; Brennan, R.; Dehejia, H.; Verebely, K.: Diphenylhydantoin
intoxication: a complication of isoniazid therapy. Am. Rev. Resp.
Dis. 101: 377-383, 1970.
15. Kutt, H.; Verebely, K.; McDowell, F.: Inhibition of diphenylhydantoin
metabolism in rat and in rat liver microsome by antitubercular drugs. Neurology 18:
706-710, 1968.
16. Kutt, H.; Wolk, M.; Scherman, R.; McDowell, F.: Insufficient
parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology 14:
542-548, 1964.
17. Laasanen, J.; Romppanen, E.-L.; Hiltunen, M.; Helisalmi, S.; Mannermaa,
A.; Punnonen, K.; Heinonen, S.: Two exonic single nucleotide polymorphisms
in the microsomal epoxide hydrolase gene are jointly associated with
preeclampsia. Europ. J. Hum. Genet. 10: 569-573, 2002.
18. McGlynn, K. A.; Rosvold, E. A.; Lustbader, E. D.; Hu, Y.; Clapper,
M. L.; Zhou, T.; Wild, C. P.; Xia, X.-L.; Baffoe-Bonnie, A.; Ofori-Adjei,
D.; Chen, G.-C.; London, W. T.; Shen, F.-M.; Buetow, K. H.: Susceptibility
to hepatocellular carcinoma is associated with genetic variation in
the enzymatic detoxification of aflatoxin B1. Proc. Nat. Acad. Sci. 92:
2384-2387, 1995.
19. Miyata, M.; Kudo, G.; Lee, Y.-H.; Yang, T. J.; Gelboin, H. V.;
Fernandez-Salguero, P.; Kimura, S.; Gonzalez, F. J.: Targeted disruption
of the microsomal epoxide hydrolase gene: microsomal epoxide hydrolase
is required for the carcinogenic activity of 7,12-dimethylbenz[alpha]anthracene. J.
Biol. Chem. 274: 23963-23968, 1999.
20. Nadeau, J. H.: Personal Communication. Bar Harbor, Me. 6/22/1988.
21. Phelan, M. C.; Pellock, J. M.; Nance, W. E.: Discordant expression
of fetal hydantoin syndrome in a pair of dizygotic twins with different
fathers. (Abstract) Am. J. Hum. Genet. 33: 67A only, 1981.
22. Sabry, M. A.; Farag, T. I.: Hand anomalies in fetal-hydantoin
syndrome: from nail/phalangeal hypoplasia to unilateral acheiria.
(Letter) Am. J. Med. Genet. 62: 410-412, 1996.
23. Sarmanova, J.; Benesova, K.; Gut, I.; Nedelcheva-Kristensen, V.;
Tynkova, L.; Soucek, P.: Genetic polymorphisms of biotransformation
enzymes in patients with Hodgkin's and non-Hodgkin's lymphomas. Hum.
Molec. Genet. 10: 1265-1273, 2001.
24. Skoda, R. C.; Demierre, A.; McBride, O. W.; Gonzalez, F. J.; Meyer,
U. A.: Human microsomal xenobiotic epoxide hydrolase: complementary
DNA sequence, complementary DNA-directed expression in COS-1 cells,
and chromosomal localization. J. Biol. Chem. 263: 1549-1554, 1988.
25. Smith, C. A. D.; Harrison, D. J.: Association between polymorphism
in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 350:
630-633, 1997.
26. Spielberg, S. P.: Personal Communication. Toronto, Ontario,
Canada 2/26/1988.
27. Spielberg, S. P.; Gordon, G. B.; Blake, D. A.; Goldstein, D. A.;
Herlong, H. F.: Predisposition to phenytoin hepatotoxicity assessed
in vitro. New Eng. J. Med. 305: 722-727, 1981.
28. Strickler, S. M.; Dansky, L. V.; Miller, M. A.; Seni, M. H.; Andermann,
E.; Spielberg, S. P.: Genetic predisposition to phenytoin-induced
birth defects. Lancet 326: 746-749, 1985. Note: Originally Volume
II.
29. Vasko, M. R.; Bell, R. D.; Daly, D. D.: Inheritance of diphenylhydantoin
hypometabolism: a pharmacokinetic study of one family. (Abstract) Clin.
Pharm. Ther. 21: 120 only, 1977.
30. Vasko, M. R.; Bell, R. D.; Daly, D. D.; Pippenger, C. E.: Inheritance
of phenyltoin hypometabolism: a kinetic study of one family. Clin.
Pharm. Ther. 27: 96-103, 1980.
31. Vermeij, P.; Ferrari, M. D.; Buruma, O. J. S.; Veenema, H.; de
Wolff, F. A.: Inheritance of poor phenytoin parahydroxylation capacity
in a Dutch family. Clin. Pharm. Ther. 44: 588-593, 1988.
32. Vesell, E. S.: Pharmacogenetics: multiple interactions between
genes and environment as determinants of drug response. (Editorial) Am.
J. Med. 66: 183-187, 1979.
33. Zhu, Q.; Xing, W.; Qian, B.; von Dippe, P.; Shneider, B. L.; Fox,
V. L.; Levy, D.: Inhibition of human m-epoxide hydrolase gene expression
in a case of hypercholanemia. Biochim. Biophys. Acta 1638: 208-216,
2003.
34. Zusterzeel, P. L. M.; Peters, W. H. M.; Visser, W.; Hermsen, K.
J. M.; Roelofs, H. M. J.; Steegers, E. A. P.: A polymorphism in the
gene for microsomal epoxide hydrolase is associated with pre-eclampsia. J.
Med. Genet. 38: 234-237, 2001.
*FIELD* CS
Misc:
Abnormal reactions to phenytoin and some other drugs;
Correlation with major birth defects
Lab:
Microsomal epoxide hydrolase defect
Inheritance:
Autosomal dominant
*FIELD* CN
Marla J. F. O'Neill - updated: 1/11/2006
Victor A. McKusick - updated: 3/1/2004
Michael B. Petersen - updated: 8/19/2003
Patricia A. Hartz - updated: 7/8/2003
Victor A. McKusick - updated: 8/23/2002
Michael J. Wright - updated: 7/1/2002
George E. Tiller - updated: 11/7/2001
Carol A. Bocchini - updated: 9/16/1999
*FIELD* CD
Victor A. McKusick: 9/28/1987
*FIELD* ED
terry: 11/27/2012
terry: 1/14/2009
terry: 9/24/2008
wwang: 1/11/2006
terry: 1/11/2006
alopez: 6/8/2005
terry: 3/16/2005
carol: 3/17/2004
tkritzer: 3/11/2004
tkritzer: 3/4/2004
terry: 3/1/2004
cwells: 8/19/2003
mgross: 7/8/2003
tkritzer: 8/28/2002
tkritzer: 8/27/2002
terry: 8/23/2002
alopez: 7/2/2002
terry: 7/1/2002
cwells: 11/20/2001
cwells: 11/7/2001
mcapotos: 11/30/2000
carol: 9/16/1999
terry: 7/24/1998
mark: 8/6/1997
terry: 8/19/1996
terry: 7/29/1996
mark: 5/12/1995
carol: 12/1/1994
mimadm: 9/24/1994
warfield: 4/8/1994
carol: 3/31/1992
supermim: 3/16/1992
*RECORD*
*FIELD* NO
132810
*FIELD* TI
+132810 EPOXIDE HYDROLASE 1, MICROSOMAL; EPHX1
;;EPOXIDE HYDROLASE; EPHX;;
EPOXIDE HYDROLASE, MICROSOMAL XENOBIOTIC; EPOX
read morePHENYTOIN TOXICITY, INCLUDED;;
ARENE OXIDE DETOXIFICATION DEFECT, INCLUDED;;
FETAL HYDANTOIN SYNDROME, INCLUDED; FHS, INCLUDED;;
DIPHENYLHYDANTOIN, DEFECT IN HYDROXYLATION OF, INCLUDED;;
LYMPHOPROLIFERATIVE DISORDERS, SUSCEPTIBILITY TO, INCLUDED
*FIELD* TX
DESCRIPTION
Epoxide hydrolases (EC 3.3.2.3) play an important role in both the
activation and detoxification of exogenous chemicals such as polycyclic
aromatic hydrocarbons.
CLONING
Jackson et al. (1987) reported the nucleotide sequence of EPOX. The
deduced protein is 455 residues long and 82% homologous to rat
microsomal epoxide hydrolase.
Skoda et al. (1988) isolated cDNA clones for human microsomal epoxide
hydrolase and determined the nucleotide sequence. The deduced amino acid
sequence of the human enzyme was found to be 80% similar to the
previously reported rabbit enzyme and 84% similar to the deduced rat
protein sequence. The N-terminal amino acids deduced from the human cDNA
were identical to the published 19 N-terminal amino acids of the
purified human enzyme. Northern blot analysis showed a single mRNA band
of 1.8 kilobases. Southern blot analysis indicated that there is only 1
copy of the gene per haploid genome. Several restriction fragment length
polymorphisms were observed with the human EPOX cDNA.
Hassett et al. (1994) isolated and sequenced clones that encoded the
entire human EPHX1 gene. The primary nuclear transcript, extending from
the start of transcription to the site of poly(A) addition, is 20,271
nucleotides long.
GENE STRUCTURE
Hassett et al. (1994) determined that the EPHX1 gene contains 9 exons
separated by 8 introns; canonical intron/exon boundary sites were
observed at each junction. The introns vary in size from 335 to 6,696
basepairs and contain numerous repetitive DNA elements, including 18 Alu
sequences (each more than 100 nucleotides long) within 4 of the introns.
MAPPING
Brown and Chalmers (1986) measured microsomal epoxide hydrolase activity
in human/mouse hybrid cells prepared from human cells expressing 6 to 7
times the activity of the mouse cells. Of 25 clones examined by
antihuman and antimouse antisera raised in the rabbit, none expressed
human enzyme. This correlated with the loss of human chromosome 6 from
each cell line. Brown and Chalmers (1986) concluded that the human gene
for epoxide hydrolase may be on chromosome 6. Certain observations in
hybrid cells suggested that other gene products can affect the level of
activity expressed by the cell. Brown and Chalmers (1986) recognized
that assignment of genes to chromosomes on the basis of negative data is
not completely satisfactory. They also observed that other chromosomes,
particularly chromosome 19, seemed to affect expression. Jackson et al.
(1987) assigned the gene to chromosome 1 by somatic cell hybridization.
Analysis of 2 hybrids containing spontaneous breaks permitted regional
localization of the gene to 1q or proximal to NRAS (164790) on 1p. By
fluorescence in situ hybridization, Hartsfield et al. (1998) mapped the
EPOX gene to 1q42.1 The mouse equivalent of EPOX, symbolized Eph-1, is
located on chromosome 1 (Nadeau, 1988).
PHENOTYPE
Strickler et al. (1985) hypothesized a mutant form of microsomal epoxide
hydrolase as the molecular basis for abnormal reactions to phenytoin and
some other drugs. Phenytoin (diphenylhydantoin, dilantin) is metabolized
by cytochrome P-450 monooxygenases to several oxidized products,
including parahydroxylated and dihydrodiol metabolites (see 124020).
Arene oxides, which are reactive electrophilic compounds, are
intermediates in these oxidative reactions. If not detoxified, arene
oxide metabolites can covalently bind to cell macromolecules, resulting
in cell death, mutation, tumors, birth defects, and, by acting as
haptens, can lead to secondary immune phenomena. In animals, toxic
effects of phenytoin, including gingival hyperplasia and teratogenicity,
have been attributed to the arene oxide metabolites.
Spielberg et al. (1981) studied individual susceptibility to toxicity
from phenytoin metabolites by exposing human lymphocytes to metabolites
generated by a murine hepatic microsomal system. Cells from 17 controls
showed no toxicity at concentrations of phenytoin from 31 to 125
micromoles. Cells from 3 patients with phenytoin hepatotoxicity
manifested dose-dependent toxicity from the metabolites. Phenytoin alone
was not toxic to cells. The patients' dose-response curves resembled the
response of control cells in which epoxide hydrolase, a detoxification
enzyme for arene oxides, was inhibited. Detoxification of non-arene
oxide metabolites (e.g., of acetaminophen) was normal in patients'
cells. Cells from parents of 2 patients had intermediate responses.
Cells from a sib of 1 patient showed no toxicity. A sib of another
patient had a response similar to that of the patient. The fetal
hydantoin syndrome has been observed in multiple sibs (e.g., Hanson et
al., 1976).
Phelan et al. (1981) observed dizygotic twins in whom the evidence of
diandric origin through superfecundation was strong (about 150 to 1).
One suspected father was black, the other white. Throughout pregnancy
the mother had taken phenobarbital and dilantin. Only 1 of the twins had
signs of the fetal hydantoin syndrome.
Strickler et al. (1985) presented evidence that they felt supported a
genetic predisposition to phenytoin-induced birth defects. Lymphocytes
from 24 children exposed to phenytoin throughout gestation and from
their families were challenged with phenytoin metabolites generated by a
mouse hepatic microsomal drug-metabolizing system. Fourteen of the
children had a positive assay result, i.e., a significant increase in
cell death associated with phenytoin metabolites. Each of these 14
children had 1 parent whose cells were also positive. A positive in
vitro challenge was highly correlated with major birth defects including
congenital heart disease, cleft lip/palate, microcephaly, and major
genitourinary, eye, and limb defects. There was no difference between
children with positive and negative results in the number or
distribution of minor birth defects and even features that have been
thought to be pathognomonic of the fetal hydantoin syndrome, such as
distal digital hypoplasia, were distributed evenly among children with
positive and negative assays. Some have questioned whether the epilepsy
rather than the drug used in its treatment is responsible for the
clinical abnormalities observed in the children of epileptic women
treated with hydantoin.
Chodirker et al. (1987) presented instructive observations of the
hydantoin effect in a child born of a nonepileptic mother who had been
given the drug during pregnancy for seizure prophylaxis after brain
surgery. Goldman et al. (1987) found that children with the fetal
hydantoin syndrome (FHS) had glucocorticoid receptor (138040) levels in
circulating lymphocytes significantly higher than those of unaffected
children with similar exposure to phenytoin. The receptor level of
affected children was also significantly elevated above that of fathers
of children with FHS and of fathers and mothers of control children. The
authors suggested that elevated levels of glucocorticoid receptors and
lymphocytes may be a marker for susceptibility to FHS.
Diphenylhydantoin is poorly excreted by the kidney. Removal from the
body depends on its hydroxylation. Kutt et al. (1964) found a family in
which 3 members had reduced ability to hydroxylate diphenylhydantoin.
The proband, who developed toxicity on usual doses of the drug, showed
accumulation of the drug and much less hydroxylated derivative than
normal in the urine. A defect in the hydroxylation of diphenylhydantoin
can be produced by simultaneous administration of isoniazid (INH) which
inhibits hydroxylation by liver microsomes (Kutt et al., 1968). Patients
who show intolerance to diphenylhydantoin when receiving INH at the same
time are patients who are the slow acetylators (243400) of INH (Kutt et
al., 1970; Brennan et al., 1970). The family reported by Kutt et al.
(1964) had a mother and 2 sons with inadequate hydroxylation. The
proband was one of the sons, a 24-year-old male without liver disease,
who consulted the authors 3 weeks after he had been given a daily dosage
of 300 mg diphenylhydantoin and 90 mg phenobarbital for control of
seizures after head injury. He showed marked nystagmus, ataxia and
mental blunting, which disappeared when diphenylhydantoin was
discontinued and reappeared when it was given again. Barbiturates alone
produce no toxicity. Vasko et al. (1977) also reported a family. The
proband was a 32-year-old epileptic who developed high blood levels and
toxicity on a moderate dose. The 24-hour urinary output of
5-(p-hydroxyphenyl)-5-phenylhydantoin was only 50% of the ingested drug.
The half-life of the drug was 32 hours. At least one child had a
prolonged half-life. Dominant inheritance was proposed by Vesell (1979).
Vasko et al. (1980) observed phenytoin hypometabolism in 4 members of 4
generations of a kindred. Presumably the defect in hydroxylation of
diphenylhydantoin (also known as phenytoin) is unrelated to the
mephenytoin-metabolizing P450 system (124020) (Spielberg, 1988).
Vermeij et al. (1988) studied the inheritance of deficient phenytoin
p-hydroxylation in the family of a patient who had previously suffered
from phenytoin intoxication caused by insufficient metabolism of this
drug (de Wolff et al., 1983). The rate of phenytoin metabolism was
derived from the phenytoin/metabolite ratio in serum 6 hours after an
oral test dose of 300 mg phenytoin. The propositus, a brother, and a
sister were very slow metabolizers of phenytoin, with a metabolic ratio
of approximately 20. All 22 children of these 3 individuals showed a
mean metabolic ratio of 6.6 (SD = 1.7), whereas a control group of 37
individuals showed a mean metabolic ratio of 3.7 (SD = 1.8).
Buehler et al. (1990) appeared to have demonstrated that low epoxide
hydrolase activity in amniocytes is a risk factor for congenital
malformations in the infants of mothers receiving phenytoin. In a random
sample of amniocytes from 100 pregnant women, thin-layer chromatography
showed an apparently trimodal distribution, suggesting that the level of
the enzyme was controlled by a single gene with 2 allelic forms. In a
prospective study of 19 pregnancies monitored by amniocentesis, an
adverse outcome was predicted for 4 fetuses on the basis of low enzyme
activity (less than 30% of the standard). In all 4 cases, the mother was
receiving phenytoin monotherapy, and, after birth, the infants had
clinical findings compatible with the fetal hydantoin syndrome. The 15
fetuses with enzyme activity above 30% of the standard were not
considered to be at risk, and all 15 neonates lacked any characteristics
of the fetal hydantoin syndrome.
Gennis et al. (1991) described 3 sibs out of 12 who developed
hypersensitivity reactions to phenytoin characterized by fever, rash,
lymphadenopathy, and anicteric hepatitis. All recovered completely after
discontinuation of treatment. One sib tolerated phenobarbital without
toxic sequelae. Peripheral blood monocytes from the 3 patients and from
5 additional sibs who had never taken anticonvulsants were exposed to
oxidative metabolites of phenytoin, phenobarbital, and carbamazepine.
The cells from each of the 3 patients demonstrated increased toxicity
from metabolites of phenytoin and carbamazepine, while the cellular
response to metabolites of phenobarbital was within normal limits. Cells
from 4 of the 5 other sibs showed an abnormal response to phenytoin
metabolites, while cells from the fifth sib detoxified phenytoin
metabolites normally.
Sabry and Farag (1996) suggested that hand anomaly in the fetal
hydantoin syndrome can be unilateral acheiria at one extreme with
nail/phalangeal hypoplasia at the other extreme. They reported the case
of a baby born with absence of the right hand with rudimentary tags at
the distal end of the right forearm. The infant was born of a
nonepileptic mother who had a history of first trimester prophylactic
anticonvulsant therapy after surgical excision of a meningioma. The
status of the nails and phalanges in the left hand was not stated.
De Smet and Debeer (2002) described 2 children whose mother had been
treated with phenylhydantoin for epilepsy that developed after surgery
for a brain tumor. The first son had hypoplasia of the terminal phalanx
of the fifth finger of the left hand. The second son was born with
severe malformation of the right hand consistent with vascular
disruption. He had facial dysmorphism with ocular hypertelorism, a small
triangular shaped skull, and a depressed nasal bridge.
MOLECULAR GENETICS
Microsomal epoxide hydrolase is a bifunctional protein that plays a
central role not only in carcinogen metabolism but is also able to
mediate the sodium-dependent uptake of bile acids into hepatocytes. Zhu
et al. (2003) studied a patient with extremely elevated serum bile salt
levels (hypercholanemia; 607748) in the absence of observable
hepatocellular injury, suggesting a defect in bile acid uptake. In this
individual, EPHX1 protein and mRNA levels were reduced by approximately
95% and 85%, respectively, whereas the expression and amino acid
sequence of another bile acid transport protein, sodium/taurocholate
cotransporting polypeptide (NTCP1; 182396), was unaffected. Sequence
analysis of the EPHX1 gene identified 2 point mutations, a -4238T-A
transversion in an upstream HNF3 site in 1 allele (132180.0003) and a
2557C-G transversion in intron 1 in the other allele (132180.0004),
which resulted in a significant decrease in EPHX1 promoter activity in
transient transfection assays.
ANIMAL MODEL
Miyata et al. (1999) determined that Ephx1-null mice were fertile and
had no phenotypic abnormalities. Ephx1-null embryonic fibroblasts were
unable to produce the carcinogenic metabolite of
7,12-dimethylbenz(alpha)anthracene (DMBA), an experimental prototype for
the polycyclic aromatic hydrocarbon class of chemical carcinogens. These
mice were resistant to DMBA-mediated toxicity and DMBA-induced
carcinogenesis.
*FIELD* AV
.0001
LYMPHOPROLIFERATIVE DISORDERS, SUSCEPTIBILITY TO
PREECLAMPSIA, SUSCEPTIBILITY TO, INCLUDED;;
EMPHYSEMA, SUSCEPTIBILITY TO, INCLUDED;;
PULMONARY DISEASE, CHRONIC OBSTRUCTIVE, SUSCEPTIBILITY TO, INCLUDED
EPHX1, TYR113HIS
Hassett et al. (1994) described a correlation between mutant alleles of
EPHX and diminished enzymatic activity. They demonstrated by in vitro
expression studies of cDNA that substitution of his113 for the more
commonly occurring tyr113 residue in exon 3 decreased EPHX activity
approximately 40%. Variation of this type may be responsible for genetic
susceptibility to the environmental carcinogen aflatoxin B1 (McGlynn et
al., 1995), and explained variation in the frequency of hepatocellular
carcinoma (HCC; 114550).
Lymphoproliferative Disorder Susceptibility
Sarmanova et al. (2001) determined the frequency of polymorphisms in
several biotransformation enzymes in patients with morbus Hodgkin and
non-Hodgkin lymphomas (NHL; 605027) and age- and sex-matched healthy
individuals. The distribution of genotypes in CYP2E1-intron 6
(124040.0002) was significantly different between the control group and
all lymphomas (P = 0.03), patients with NHL (P = 0.024), and especially
aggressive diffuse NHL (P = 0.007). The EPHX-exon 3 genotype
distribution was significantly different between control males and males
with all lymphomas (P = 0.01) or with NHL (P = 0.019). The authors
suggested that genetic polymorphisms of biotransformation enzymes may
play a significant role in the development of lymphoid malignancies.
Preeclampsia Susceptibility
Zusterzeel et al. (2001) studied genetic variability of the EPHX1 gene
in women with a history of preeclampsia (189800). They found a
significantly higher frequency of the high activity tyr113/tyr113
genotype (odds ratio 2.0, 95% C.I. 1.2-3.7) in women with a history of
preeclampsia compared to controls.
Chronic Obstructive Pulmonary Disease (COPD) and Emphysema
Susceptibility
Smith and Harrison (1997) studied EPHX1 polymorphisms in patients with
various pulmonary diseases and found that the very slow phenotype
(his113) was 4 to 5 times more common in patients with COPD or emphysema
compared to controls.
.0002
EPOXIDE HYDROLASE POLYMORPHISM
EPHX1, HIS139ARG
Laasanen et al. (2002) studied an A-G polymorphism (his139 to arg) in
exon 4 of the EPHX1 gene in 133 Finnish preeclamptic and 115 healthy
control women with at least 2 normal pregnancies. Genotype and allele
distributions did not reveal statistically significant single-point
association with preeclampsia (189800). However, haplotype analysis
using this polymorphism and the exon 3 T-C polymorphism (tyr113 to his;
132810.0001) showed that the high activity haplotype T/A (tyr113/his139)
was significantly overrepresented in the preeclampsia group (P = 0.01;
odds ratio 1.61, 95% C.I. 1.12-2.32).
.0003
HYPERCHOLANEMIA, FAMILIAL
EPHX1, -4238T-A
In a patient with hypercholanemia (607748) in the absence of observable
hepatocellular injury, suggesting a defect in bile acid uptake, Zhu et
al. (2003) identified compound heterozygosity for mutations in the EPHX1
gene: one allele had a -4238T-A transversion in the 5-prime region at a
putative HNF3 site inherited from the father, and the other had a
2557C-G transversion in intron 1 (132810.0004). Both mutations
significantly decreased EPHX1 promoter activity. EPHX1 protein and mRNA
levels were reduced by approximately 95% and 85%, respectively. The
existence of both mutant alleles appeared to be necessary for the
observed hypercholanemia, since the father, who possessed only the
-4238T-A transversion, had normal serum glycocholate levels.
.0004
HYPERCHOLANEMIA, FAMILIAL
EPHX1, 2557C-G
See 132810.0003 and Zhu et al. (2003).
*FIELD* RF
1. Brennan, R. W.; Dehejia, H.; Kutt, H.; Verebely, K.; McDowell,
F.: Diphenylhydantoin intoxication attendant to slow inactivation
of isoniazid. Neurology 20: 687-693, 1970.
2. Brown, S.; Chalmers, D. E.: Microsomal epoxide hydrolase activity
in human x mouse hybrid cells. Biochem. Biophys. Res. Commun. 137:
775-780, 1986.
3. Buehler, B. A.; Delimont, D.; van Waes, M.; Finnell, R. H.: Prenatal
prediction of risk of the fetal hydantoin syndrome. New Eng. J. Med. 322:
1567-1571, 1990.
4. Chodirker, B. N.; Chudley, A. E.; Reed, M. H.; Persaud, T. V. N.
: Possible prenatal hydantoin effect in a child born to a nonepileptic
mother. Am. J. Med. Genet. 27: 373-378, 1987.
5. De Smet, L.; Debeer, P.: Fetal hydantoin syndrome with unilateral
atypical cleft hand: additional evidence for vascular disruption. Genet.
Counsel. 13: 157-161, 2002.
6. de Wolff, F. A.; Vermeij, P.; Ferrari, M. D.; Buruma, O. J. S.;
Breimer, D. D.: Impairment of phenytoin parahydroxylation as a cause
of severe intoxication. Ther. Drug Monit. 5: 213-215, 1983.
7. Gennis, M. A.; Vemuri, R.; Burns, E. A.; Hill, J. V.; Miller, M.
A.; Spielberg, S. P.: Familial occurrence of hypersensitivity to
phenytoin. Am. J. Med. 91: 631-634, 1991.
8. Goldman, A. S.; Van Dyke, D. C.; Gupta, C.; Katsumata, M.: Elevated
glucocorticoid receptor levels in lymphocytes of children with the
fetal hydantoin syndrome (FHS). Am. J. Med. Genet. 28: 607-618,
1987.
9. Hanson, J. W.; Myrianthopoulos, N. C.; Sedgwick, M. H. A.; Smith,
D. W.: Risks to the offspring of women treated with hydantoin anticonvulsants,
with emphasis on the fetal hydantoin syndrome. J. Pediat. 89: 662-668,
1976.
10. Hartsfield, J. K., Jr.; Sutcliffe, M. J.; Everett, E. T.; Hassett,
C.; Omiecinski, C. J.; Saari, J. A.: Assignment of microsomal epoxide
hydrolase (EPHX1) to human chromosome 1q42.1 by in situ hybridization. Cytogenet.
Cell Genet. 83: 44-45, 1998.
11. Hassett, C.; Aicher, L.; Sidhu, J. S.; Omiecinski, C. J.: Human
microsomal epoxide hydrolase: genetic polymorphism and functional
expression in vitro of amino acid variants. Hum. Molec. Genet. 3:
421-428, 1994. Note: Erratum: Hum. Molec. Genet. 3: 1214 only, 1994.
12. Hassett, C.; Robinson, K. B.; Beck, N. B.; Omiecinski, C. J.:
The human microsomal epoxide hydrolase gene (EPHX1): complete nucleotide
sequence and structural characterization. Genomics 23: 433-442,
1994.
13. Jackson, M. R.; Craft, J. A.; Burchell, B.: Nucleotide and deduced
amino acid sequence of human liver microsomal epoxide hydrolase. Nucleic
Acids Res. 15: 7188 only, 1987.
14. Kutt, H.; Brennan, R.; Dehejia, H.; Verebely, K.: Diphenylhydantoin
intoxication: a complication of isoniazid therapy. Am. Rev. Resp.
Dis. 101: 377-383, 1970.
15. Kutt, H.; Verebely, K.; McDowell, F.: Inhibition of diphenylhydantoin
metabolism in rat and in rat liver microsome by antitubercular drugs. Neurology 18:
706-710, 1968.
16. Kutt, H.; Wolk, M.; Scherman, R.; McDowell, F.: Insufficient
parahydroxylation as a cause of diphenylhydantoin toxicity. Neurology 14:
542-548, 1964.
17. Laasanen, J.; Romppanen, E.-L.; Hiltunen, M.; Helisalmi, S.; Mannermaa,
A.; Punnonen, K.; Heinonen, S.: Two exonic single nucleotide polymorphisms
in the microsomal epoxide hydrolase gene are jointly associated with
preeclampsia. Europ. J. Hum. Genet. 10: 569-573, 2002.
18. McGlynn, K. A.; Rosvold, E. A.; Lustbader, E. D.; Hu, Y.; Clapper,
M. L.; Zhou, T.; Wild, C. P.; Xia, X.-L.; Baffoe-Bonnie, A.; Ofori-Adjei,
D.; Chen, G.-C.; London, W. T.; Shen, F.-M.; Buetow, K. H.: Susceptibility
to hepatocellular carcinoma is associated with genetic variation in
the enzymatic detoxification of aflatoxin B1. Proc. Nat. Acad. Sci. 92:
2384-2387, 1995.
19. Miyata, M.; Kudo, G.; Lee, Y.-H.; Yang, T. J.; Gelboin, H. V.;
Fernandez-Salguero, P.; Kimura, S.; Gonzalez, F. J.: Targeted disruption
of the microsomal epoxide hydrolase gene: microsomal epoxide hydrolase
is required for the carcinogenic activity of 7,12-dimethylbenz[alpha]anthracene. J.
Biol. Chem. 274: 23963-23968, 1999.
20. Nadeau, J. H.: Personal Communication. Bar Harbor, Me. 6/22/1988.
21. Phelan, M. C.; Pellock, J. M.; Nance, W. E.: Discordant expression
of fetal hydantoin syndrome in a pair of dizygotic twins with different
fathers. (Abstract) Am. J. Hum. Genet. 33: 67A only, 1981.
22. Sabry, M. A.; Farag, T. I.: Hand anomalies in fetal-hydantoin
syndrome: from nail/phalangeal hypoplasia to unilateral acheiria.
(Letter) Am. J. Med. Genet. 62: 410-412, 1996.
23. Sarmanova, J.; Benesova, K.; Gut, I.; Nedelcheva-Kristensen, V.;
Tynkova, L.; Soucek, P.: Genetic polymorphisms of biotransformation
enzymes in patients with Hodgkin's and non-Hodgkin's lymphomas. Hum.
Molec. Genet. 10: 1265-1273, 2001.
24. Skoda, R. C.; Demierre, A.; McBride, O. W.; Gonzalez, F. J.; Meyer,
U. A.: Human microsomal xenobiotic epoxide hydrolase: complementary
DNA sequence, complementary DNA-directed expression in COS-1 cells,
and chromosomal localization. J. Biol. Chem. 263: 1549-1554, 1988.
25. Smith, C. A. D.; Harrison, D. J.: Association between polymorphism
in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 350:
630-633, 1997.
26. Spielberg, S. P.: Personal Communication. Toronto, Ontario,
Canada 2/26/1988.
27. Spielberg, S. P.; Gordon, G. B.; Blake, D. A.; Goldstein, D. A.;
Herlong, H. F.: Predisposition to phenytoin hepatotoxicity assessed
in vitro. New Eng. J. Med. 305: 722-727, 1981.
28. Strickler, S. M.; Dansky, L. V.; Miller, M. A.; Seni, M. H.; Andermann,
E.; Spielberg, S. P.: Genetic predisposition to phenytoin-induced
birth defects. Lancet 326: 746-749, 1985. Note: Originally Volume
II.
29. Vasko, M. R.; Bell, R. D.; Daly, D. D.: Inheritance of diphenylhydantoin
hypometabolism: a pharmacokinetic study of one family. (Abstract) Clin.
Pharm. Ther. 21: 120 only, 1977.
30. Vasko, M. R.; Bell, R. D.; Daly, D. D.; Pippenger, C. E.: Inheritance
of phenyltoin hypometabolism: a kinetic study of one family. Clin.
Pharm. Ther. 27: 96-103, 1980.
31. Vermeij, P.; Ferrari, M. D.; Buruma, O. J. S.; Veenema, H.; de
Wolff, F. A.: Inheritance of poor phenytoin parahydroxylation capacity
in a Dutch family. Clin. Pharm. Ther. 44: 588-593, 1988.
32. Vesell, E. S.: Pharmacogenetics: multiple interactions between
genes and environment as determinants of drug response. (Editorial) Am.
J. Med. 66: 183-187, 1979.
33. Zhu, Q.; Xing, W.; Qian, B.; von Dippe, P.; Shneider, B. L.; Fox,
V. L.; Levy, D.: Inhibition of human m-epoxide hydrolase gene expression
in a case of hypercholanemia. Biochim. Biophys. Acta 1638: 208-216,
2003.
34. Zusterzeel, P. L. M.; Peters, W. H. M.; Visser, W.; Hermsen, K.
J. M.; Roelofs, H. M. J.; Steegers, E. A. P.: A polymorphism in the
gene for microsomal epoxide hydrolase is associated with pre-eclampsia. J.
Med. Genet. 38: 234-237, 2001.
*FIELD* CS
Misc:
Abnormal reactions to phenytoin and some other drugs;
Correlation with major birth defects
Lab:
Microsomal epoxide hydrolase defect
Inheritance:
Autosomal dominant
*FIELD* CN
Marla J. F. O'Neill - updated: 1/11/2006
Victor A. McKusick - updated: 3/1/2004
Michael B. Petersen - updated: 8/19/2003
Patricia A. Hartz - updated: 7/8/2003
Victor A. McKusick - updated: 8/23/2002
Michael J. Wright - updated: 7/1/2002
George E. Tiller - updated: 11/7/2001
Carol A. Bocchini - updated: 9/16/1999
*FIELD* CD
Victor A. McKusick: 9/28/1987
*FIELD* ED
terry: 11/27/2012
terry: 1/14/2009
terry: 9/24/2008
wwang: 1/11/2006
terry: 1/11/2006
alopez: 6/8/2005
terry: 3/16/2005
carol: 3/17/2004
tkritzer: 3/11/2004
tkritzer: 3/4/2004
terry: 3/1/2004
cwells: 8/19/2003
mgross: 7/8/2003
tkritzer: 8/28/2002
tkritzer: 8/27/2002
terry: 8/23/2002
alopez: 7/2/2002
terry: 7/1/2002
cwells: 11/20/2001
cwells: 11/7/2001
mcapotos: 11/30/2000
carol: 9/16/1999
terry: 7/24/1998
mark: 8/6/1997
terry: 8/19/1996
terry: 7/29/1996
mark: 5/12/1995
carol: 12/1/1994
mimadm: 9/24/1994
warfield: 4/8/1994
carol: 3/31/1992
supermim: 3/16/1992
MIM
607748
*RECORD*
*FIELD* NO
607748
*FIELD* TI
#607748 HYPERCHOLANEMIA, FAMILIAL; FHCA
*FIELD* TX
A number sign (#) is used with this entry because hypercholanemia can be
read morecaused by mutation in the TJP2 gene (607709) on chromosome 9q21, the
BAAT gene (602938) on chromosome 9q31, or the EPHX1 gene (132810) on
chromosome 1q42.
CLINICAL FEATURES
Familial hypercholanemia is characterized by elevated serum bile acid
concentrations, itching, and fat malabsorption (Morton et al., 2000;
Shneider et al., 1997). Carlton et al. (2003) identified 17 individuals
with familial hypercholanemia in 12 families of Lancaster County Old
Order Amish descent. Serum bile acid concentration in affected
individuals fluctuated, being often very high but occasionally normal.
Fat malabsorption, reflecting low intestinal bile acid levels,
manifested by failure to thrive, potentially life-threatening vitamin
K-dependent coagulopathy, and rickets. Symptoms usually responded to
treatment with ursodeoxycholic acid (UDCA). Familial hypercholanemia is
atypical for a liver disease; test results of biochemical markers of
liver injury were normal, except for alkaline phosphatase activity,
which sometimes rose. Liver biopsy findings varied; 1 untreated
individual had canalicular cholestasis and 2 individuals receiving UDCA
had minimally active chronic hepatitis. Several older individuals had
become symptom-free and discontinued UDCA treatment.
MOLECULAR GENETICS
By whole-genome screen, Carlton et al. (2003) identified a chromosomal
region, 9q12-q13, shared identically by descent (IBD) on 6 of 10
chromosomes of affected individuals included in the initial analysis.
The gene encoding tight junction protein-2 (TJP2; 607709) lies within
the 9q12-q13 region. Genomic sequencing of exons and exon-intron
boundaries of TJP2 in 1 affected individual identified a val48-to-ala
mutation in TJP2 (V48A; 607709.0001). Screening of all 17 individuals
with familial hypercholanemia showed that 11 (including a pair of
monozygotic twins) in 8 families were homozygous with respect to the
V48A mutation. Three unaffected sibs were also homozygous, showing that
penetrance was incomplete. The mutation was not present in 190 control
chromosomes from Caucasian individuals. It was seen on 7 of 104 control
chromosomes from Lancaster County Old Order Amish individuals.
In 4 individuals with familial hypercholanemia who did not have the TJP2
V48A mutation, Carlton et al. (2003) identified an IBD haplotype in
9q22-q32, a region containing the candidate gene BAAT (602938). Genomic
sequencing of exons and exon-intron boundaries of BAAT in 1 individual
identified a met76-to-val (M76V; 602938.0001) mutation. Screening of all
17 individuals with hypercholanemia identified 5 individuals (in 3
families) who were homozygous with respect to this mutation. Several
individuals who were homozygous for the TJP2 V48A mutation were also
heterozygous for the BAAT M76V mutation. The BAAT mutation was not seen
in 182 control chromosomes from Caucasian subjects and was seen in only
1 of 104 control chromosomes from Lancaster County Old Order Amish
individuals.
Carlton et al. (2003) found 1 individual with familial hypercholanemia
who did not have either mutation (TJP2 V48A or BAAT M76V) and was not
homozygous in either region on chromosome 9. That several individuals
carried mutations in both genes suggested oligogenic inheritance.
In a patient with hypercholanemia, Zhu et al. (2003) identified compound
heterozygosity for 2 mutations in the EPHX1 gene (see 132180.0003),
which resulted in a significant decrease in EPHX1 promoter activity.
PATHOGENESIS
Carlton et al. (2003) postulated that in individuals homozygous for the
BAAT M76V mutation, bile acids do not traverse hepatocytes into bile. In
contrast, they believed that in individuals homozygous for the TJP2 V48A
mutation, bile acids enter bile and then leak through tight junctions
into plasma.
NOMENCLATURE
Carlton et al. (2003) used FHC as the symbol for familial
hypercholanemia. This is an unfortunate and potentially confusing usage
since FHC has a long track record as the abbreviation for familial
hypercholesterolemia (143890).
*FIELD* RF
1. Carlton, V. E. H.; Harris, B. Z.; Puffenberg, E. G.; Batta, A.
K.; Knisely, A. S.; Robinson, D. L.; Strauss, K. A.; Shneider, B.
L.; Lim, W. A.; Salen, G.; Morton, D. H.; Bull, L. N.: Complex inheritance
of familial hypercholanemia with associated mutations in TJP2 and
BAAT. Nature Genet. 34: 91-96, 2003.
2. Morton, D. H.; Salen, G.; Batta, A. K.; Shefer, S.; Tint, G. S.;
Belchis, D.; Shneider, B.; Puffenberger, E.; Bull, L.; Knisely, A.
S.: Abnormal hepatic sinusoidal bile acid transport in an Amish kindred
is not linked to FIC1 and is improved by ursodiol. Gastroenterology 119:
188-195, 2000.
3. Shneider, B. L.; Fox, V. L.; Schwarz, K. B.; Watson, C. L.; Ananthanarayanan,
M.; Thevananther, S.; Christie, D. M.; Hardikar, W.; Setchell, K.
D. R.; Mieli-Vergani, G.; Suchy, F. J.; Mowat, A. P.: Hepatic basolateral
sodium-dependent-bile acid transporter expression in two unusual cases
of hypercholanemia and in extrahepatic biliary atresia. Hepatology 25:
1176-1183, 1997.
4. Zhu, Q.; Xing, W.; Qian, B.; von Dippe, P.; Shneider, B. L.; Fox,
V. L.; Levy, D.: Inhibition of human m-epoxide hydrolase gene expression
in a case of hypercholanemia. Biochim. Biophys. Acta 1638: 208-216,
2003.
*FIELD* CN
Victor A. McKusick - updated: 3/1/2004
*FIELD* CD
Victor A. McKusick: 5/2/2003
*FIELD* ED
terry: 07/27/2012
carol: 4/30/2012
terry: 3/26/2012
terry: 8/25/2006
tkritzer: 3/11/2004
tkritzer: 3/4/2004
terry: 3/1/2004
alopez: 5/5/2003
*RECORD*
*FIELD* NO
607748
*FIELD* TI
#607748 HYPERCHOLANEMIA, FAMILIAL; FHCA
*FIELD* TX
A number sign (#) is used with this entry because hypercholanemia can be
read morecaused by mutation in the TJP2 gene (607709) on chromosome 9q21, the
BAAT gene (602938) on chromosome 9q31, or the EPHX1 gene (132810) on
chromosome 1q42.
CLINICAL FEATURES
Familial hypercholanemia is characterized by elevated serum bile acid
concentrations, itching, and fat malabsorption (Morton et al., 2000;
Shneider et al., 1997). Carlton et al. (2003) identified 17 individuals
with familial hypercholanemia in 12 families of Lancaster County Old
Order Amish descent. Serum bile acid concentration in affected
individuals fluctuated, being often very high but occasionally normal.
Fat malabsorption, reflecting low intestinal bile acid levels,
manifested by failure to thrive, potentially life-threatening vitamin
K-dependent coagulopathy, and rickets. Symptoms usually responded to
treatment with ursodeoxycholic acid (UDCA). Familial hypercholanemia is
atypical for a liver disease; test results of biochemical markers of
liver injury were normal, except for alkaline phosphatase activity,
which sometimes rose. Liver biopsy findings varied; 1 untreated
individual had canalicular cholestasis and 2 individuals receiving UDCA
had minimally active chronic hepatitis. Several older individuals had
become symptom-free and discontinued UDCA treatment.
MOLECULAR GENETICS
By whole-genome screen, Carlton et al. (2003) identified a chromosomal
region, 9q12-q13, shared identically by descent (IBD) on 6 of 10
chromosomes of affected individuals included in the initial analysis.
The gene encoding tight junction protein-2 (TJP2; 607709) lies within
the 9q12-q13 region. Genomic sequencing of exons and exon-intron
boundaries of TJP2 in 1 affected individual identified a val48-to-ala
mutation in TJP2 (V48A; 607709.0001). Screening of all 17 individuals
with familial hypercholanemia showed that 11 (including a pair of
monozygotic twins) in 8 families were homozygous with respect to the
V48A mutation. Three unaffected sibs were also homozygous, showing that
penetrance was incomplete. The mutation was not present in 190 control
chromosomes from Caucasian individuals. It was seen on 7 of 104 control
chromosomes from Lancaster County Old Order Amish individuals.
In 4 individuals with familial hypercholanemia who did not have the TJP2
V48A mutation, Carlton et al. (2003) identified an IBD haplotype in
9q22-q32, a region containing the candidate gene BAAT (602938). Genomic
sequencing of exons and exon-intron boundaries of BAAT in 1 individual
identified a met76-to-val (M76V; 602938.0001) mutation. Screening of all
17 individuals with hypercholanemia identified 5 individuals (in 3
families) who were homozygous with respect to this mutation. Several
individuals who were homozygous for the TJP2 V48A mutation were also
heterozygous for the BAAT M76V mutation. The BAAT mutation was not seen
in 182 control chromosomes from Caucasian subjects and was seen in only
1 of 104 control chromosomes from Lancaster County Old Order Amish
individuals.
Carlton et al. (2003) found 1 individual with familial hypercholanemia
who did not have either mutation (TJP2 V48A or BAAT M76V) and was not
homozygous in either region on chromosome 9. That several individuals
carried mutations in both genes suggested oligogenic inheritance.
In a patient with hypercholanemia, Zhu et al. (2003) identified compound
heterozygosity for 2 mutations in the EPHX1 gene (see 132180.0003),
which resulted in a significant decrease in EPHX1 promoter activity.
PATHOGENESIS
Carlton et al. (2003) postulated that in individuals homozygous for the
BAAT M76V mutation, bile acids do not traverse hepatocytes into bile. In
contrast, they believed that in individuals homozygous for the TJP2 V48A
mutation, bile acids enter bile and then leak through tight junctions
into plasma.
NOMENCLATURE
Carlton et al. (2003) used FHC as the symbol for familial
hypercholanemia. This is an unfortunate and potentially confusing usage
since FHC has a long track record as the abbreviation for familial
hypercholesterolemia (143890).
*FIELD* RF
1. Carlton, V. E. H.; Harris, B. Z.; Puffenberg, E. G.; Batta, A.
K.; Knisely, A. S.; Robinson, D. L.; Strauss, K. A.; Shneider, B.
L.; Lim, W. A.; Salen, G.; Morton, D. H.; Bull, L. N.: Complex inheritance
of familial hypercholanemia with associated mutations in TJP2 and
BAAT. Nature Genet. 34: 91-96, 2003.
2. Morton, D. H.; Salen, G.; Batta, A. K.; Shefer, S.; Tint, G. S.;
Belchis, D.; Shneider, B.; Puffenberger, E.; Bull, L.; Knisely, A.
S.: Abnormal hepatic sinusoidal bile acid transport in an Amish kindred
is not linked to FIC1 and is improved by ursodiol. Gastroenterology 119:
188-195, 2000.
3. Shneider, B. L.; Fox, V. L.; Schwarz, K. B.; Watson, C. L.; Ananthanarayanan,
M.; Thevananther, S.; Christie, D. M.; Hardikar, W.; Setchell, K.
D. R.; Mieli-Vergani, G.; Suchy, F. J.; Mowat, A. P.: Hepatic basolateral
sodium-dependent-bile acid transporter expression in two unusual cases
of hypercholanemia and in extrahepatic biliary atresia. Hepatology 25:
1176-1183, 1997.
4. Zhu, Q.; Xing, W.; Qian, B.; von Dippe, P.; Shneider, B. L.; Fox,
V. L.; Levy, D.: Inhibition of human m-epoxide hydrolase gene expression
in a case of hypercholanemia. Biochim. Biophys. Acta 1638: 208-216,
2003.
*FIELD* CN
Victor A. McKusick - updated: 3/1/2004
*FIELD* CD
Victor A. McKusick: 5/2/2003
*FIELD* ED
terry: 07/27/2012
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terry: 3/1/2004
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