Alternative titles; symbols
HGNC Approved Gene Symbol: CYP2E1
Cytogenetic location: 10q26.3 Genomic coordinates (GRCh38): 10:133,527,363-133,539,123 (from NCBI)
The CYP2E1 gene encodes an enzyme (EC 1.14.13.-) involved in the metabolism of drugs, hormones, and xenobiotic toxins (Wang et al., 2009).
Klingenberg (1958) and Garfinkel (1958) first discovered a hepatic microsomal carbon monoxide-binding pigment with an absorption spectrum of 450 nm. That the pigment was a cytochrome was shown by Omura and Sato (1962), who designated it P-450.
The P450IIE subfamily is ethanol-inducible. It has at least 1 gene, and a second is likely in rat and in man (Nebert et al., 1987).
Song et al. (1986) isolated cDNAs encoding ethanol-inducible forms of rat and human P450s. On the basis of the sequence, it was concluded that both the rat and human proteins contain 493 amino acids and calculated molecular masses of 56.6 and 56.9 kD, respectively. They also described a TaqI polymorphism of this gene.
Using the rabbit liver progesterone-21-hydroxylase P-450 1 cDNA as a probe, Okino et al. (1987) identified a highly homologous (81% within the coding region) human liver cDNA that encodes a 490-amino acid protein. The protein shows 82% homology to the mephenytoin 4-hydroxylase (CYP2C; 124020).
Umeno et al. (1988) presented the complete gene sequence. The human gene spans 11,413 basepairs and contains 9 exons and a typical TATA box. A full-length cDNA, constructed with the first exon of the genomic clone and a partial cDNA clone, was expressed in COS cells and found to code for N-nitrosodimethylamine demethylase activity.
Using a panel of somatic cell hybrids, McBride et al. (1987) localized the gene to chromosome 10.
By hybridization to a panel of human-rodent somatic cell hybrids, Okino et al. (1987) mapped the CYP2E gene to chromosome 10.
Kolble (1993) used an intronic (GGAT)n-(CCTA)n repeat element as a sequence tagged site for genomic amplification from somatic cell hybrids to localize the CYP2E gene to chromosome 10q24.3-qter. The close synteny of CYP2E, CYP2C, and CYP17 (609300), belonging to 2 different cytochrome P450 families, was noteworthy. Kolble (1993) suggested that the linkage group ancestral to human chromosome 10 may have contained the primordial cytochrome P450 gene that has evolved in cycles of local duplication and chromosomal dispersion.
Watanabe et al. (1990) described RFLPs at the CYP2E locus. CYP2E is involved in the metabolism of nitrosamines. Due to the possible correlation of both CYP2D (124030) and CYP2E genes with malignancy, clinical studies of RFLP patterns of these genes in cancer may be useful.
Hayashi et al. (1991) identified genetic polymorphisms in the 5-prime flanking region of the human P450IIE1 gene (124040.0001) and investigated the effect of these polymorphisms on the transcriptional regulation of the gene. They found that the polymorphisms affected its binding of transacting factor and changed its transcriptional regulation. They suggested that this may lead to interindividual differences of microsomal drug oxidation activity.
Alcohol dehydrogenase-2 (ADH2, or ADH1B; 103720), aldehyde dehydrogenase-2 (ALDH2; 100650), and CYP2E1 are important enzymes for the catalysis of the conversion of ethanol to acetaldehyde and to acetate in humans. Genetic polymorphisms have been reported in ADH2 and ALDH2, as well as in CYP2E1 (Hayashi et al., 1991). Acetaldehyde is known to play a major role in producing unpleasant symptoms after alcohol intake, such as facial flushing, palpitations, headache, vomiting, and sweating, and in the development of alcohol liver disease. The accumulation of acetaldehyde in liver and blood after drinking alcohol must be determined by the relative rates of its formation and removal, which are influenced by the interactive action of the 3 enzymes. It is well established that polymorphisms of ALDH2 have a strong relationship with individual drinking behaviors in the Asian population, because inactive ALDH2 produced by the ALDH2*2 allele (100650.0001) delays the elimination of acetaldehyde and provides a genetic protection against heavy drinking in Asians, encoding about half of the Japanese and Chinese populations. The effects of polymorphisms of ADH2 and CYP2E1 had been studied but remained controversial, even in the same ethnic group. The interaction of the 3 genetic effects is obviously of relevance. Tanaka et al. (1997) observed that individuals with the c2/c2 (124040.0001) genotype at the CYP2E1 locus could consume more ethanol on average than those with the c1/c1 genotype in subjects homozygous for the ALDH2*1 homozygous genotype, suggesting an interactive effect between ADLH2 and CYP2E1 on alcohol consumption in healthy Japanese men. To evaluate the independent and interactive effects of the genetic polymorphisms of ALDH2, ADH2, and CYP2E1 in relation to alcohol consumption large enough to cause adverse health effects, Sun et al. (1999) analyzed 643 healthy Japanese men for genotype and drinking habits. They showed that Japanese men with the ALDH2*1 homozygous genotype and the c2 allele of CYP2E1 are at a higher risk of showing excessive alcohol consumption.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of 3 combined genotypes, 1 for predicted CYP2C19 (124020) poor metabolizers (CYP2C19*2/CYP2C19*3) and 2 for predicted high levels of CYP2E1 (124040) (CYP2E1*5B and CYP2E1*6) transcription, were significantly lower in the Chinese Kazakh (7.5%, 19.6%, and 28.0%, respectively) and Uygur (8.1%, 22.8%, and 33.6%) populations compared to the Chinese Han population (16.5%, 35.9%, and 44.7%). The findings suggested that disease susceptibilities or drug responses associated with enzyme activities of CYP2C19 and CYP2E1 may differ between ethnic populations of mainland China.
This SNP, combining a -1293G-C transversion (rs3813867) and a -1053C-T transition (rs2031920) in the 5-prime transcriptional regulatory region of the CYP2E1 gene, is referred to as CYP2E1*5B (Wang et al., 2009).
This allele is associated with increased transcription of CYP2E1 (Wang et al., 2009).
Hayashi et al. (1991) described a polymorphism in the 5-prime flanking region of CYP2E, and the alleles were designated c1 (RsaI+) and c2 (RsaI-). Sun et al. (1999) observed that Japanese men with the homozygous ALDH2*1 genotype (see 100650) and the c2 allele of CYP2E were at a higher risk of excessive alcohol consumption.
In a population-based study of 359 unrelated mainland Chinese, consisting of 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the CYP2E1*5B polymorphism were significantly lower in the Kazakh and Uygur populations (11.2% and 12.1%, respectively) compared to the Han population (19.4%).
This SNP, a 7643T-A transversion in intron 6 of the CYP2E1 gene (rs6413432), is referred to as CYP2E1*6 (Wang et al., 2009).
This allele is associated with increased transcription of CYP2E1 (Wang et al., 2009). In a population-based study of 359 unrelated mainland Chinese, consisting 103 Han, 107 Kazakh, and 149 Uygur individuals, Wang et al. (2009) found that the frequencies of the CYP2E1*6 polymorphism were significantly lower in the Kazakh and Uygur populations (14.5% and 18.8%, respectively) compared to the Han population (26.2%%).
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 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 (132810.0001) 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.
Garfinkel, D. Studies on pig liver microsomes. 1. Enzymic and pigment composition of different microsomal fractions. Arch. Biochem. Biophys. 77: 493-509, 1958. [PubMed: 13584011] [Full Text: https://doi.org/10.1016/0003-9861(58)90095-x]
Hayashi, S., Watanabe, J., Kawajiri, K. Genetic polymorphisms in the 5-prime-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J. Biochem. 110: 559-565, 1991. [PubMed: 1778977] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a123619]
Klingenberg, M. Pigments of rat liver microsomes. Arch. Biochem. Biophys. 75: 376-386, 1958. [PubMed: 13534720] [Full Text: https://doi.org/10.1016/0003-9861(58)90436-3]
Kolble, K. Regional mapping of short tandem repeats on human chromosome 10: cytochrome P450 gene CYP2E, D10S196, D10S220, and D10S225. Genomics 18: 702-704, 1993. [PubMed: 8307581] [Full Text: https://doi.org/10.1016/s0888-7543(05)80378-7]
McBride, O. W., Umeno, M., Gelboin, H. V., Gonzalez, F. J. A TaqI polymorphism in the human P450IIE1 gene on chromosome 10 (CYP2E). Nucleic Acids Res. 15: 10071, 1987. [PubMed: 2892165] [Full Text: https://doi.org/10.1093/nar/15.23.10071]
Nebert, D. W., Adesnik, M., Coon, M. J., Estabrook, R. W., Gonzalez, F. J., Guengerich, F. P., Gunsalus, I. C., Johnson, E. F., Kemper, B., Levin, W., Phillips, I. R., Sato, R., Waterman, M. R. The P450 gene superfamily: recommended nomenclature. DNA 6: 1-11, 1987. [PubMed: 3829886] [Full Text: https://doi.org/10.1089/dna.1987.6.1]
Okino, S. T., Quattrochi, L. C., Pendurthi, U. R., McBride, O. W., Tukey, R. H. Characterization of multiple human cytochrome P-450 1 cDNAs: the chromosomal localization of the gene and evidence for alternate RNA splicing. J. Biol. Chem. 262: 16072-16079, 1987. Note: Erratum: J. Biol. Chem. 263: 2576 only, 1988. [PubMed: 3500169]
Omura, T., Sato, R. A new cytochrome in liver microsomes. J. Biol. Chem. 237: 1375-1376, 1962. [PubMed: 14482007]
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. [PubMed: 11406608] [Full Text: https://doi.org/10.1093/hmg/10.12.1265]
Song, B.-J., Gelboin, H. V., Park, S.-S., Yang, C. S., Gonzalez, F. J. Complementary DNA and protein sequences of ethanol-inducible rat and human cytochrome P-450s: transcriptional and post-transcriptional regulation of the rat enzyme. J. Biol. Chem. 261: 16689-16697, 1986. Note: Erratum: J. Biol. Chem. 262: 8940, 1987. [PubMed: 3782137]
Sun, F., Tsuritani, I., Honda, R., Ma, Z.-Y., Yamada, Y. Association of genetic polymorphisms of alcohol-metabolizing enzymes with excessive alcohol consumption in Japanese men. Hum. Genet. 105: 295-300, 1999. [PubMed: 10543395] [Full Text: https://doi.org/10.1007/s004399900133]
Tanaka, F., Shiratori, Y., Yokosuka, O., Imazeki, F., Tsukada, Y., Omata, M. Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men. Alcohol. Clin. Exp. Res. 21: 596-601, 1997. [PubMed: 9194910]
Umeno, M., McBride, O. W., Yang, C. S., Gelboin, H. V., Gonzalez, F. J. Human ethanol-inducible P450IIE1: complete gene sequence, promoter characterization, chromosome mapping, and cDNA-directed expression. Biochemistry 27: 9006-9013, 1988. [PubMed: 3233219] [Full Text: https://doi.org/10.1021/bi00425a019]
Wang, S.-M., Zhu, A.-P., Li, D., Wang, Z., Zhang, P., Zhang, G.-L. Frequencies of genotypes and alleles of the functional SNPs in CYP2C19 and CYP2E1 in mainland Chinese Kazakh, Uygur and Han populations. J. Hum. Genet. 54: 372-375, 2009. [PubMed: 19444287] [Full Text: https://doi.org/10.1038/jhg.2009.41]
Watanabe, J., Hayashi, S.-I., Nakachi, K., Imai, K., Suda, Y., Sekine, T., Kawajiri, K. PstI and RsaI RFLPs in complete linkage disequilibrium at the CYP2E gene. Nucleic Acids Res. 18: 7194, 1990. [PubMed: 1979861] [Full Text: https://doi.org/10.1093/nar/18.23.7194]