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HGNC Approved Gene Symbol: CYP1A2
Cytogenetic location: 15q24.1 Genomic coordinates (GRCh38): 15:74,748,845-74,756,607 (from NCBI)
The CYP1A2 gene encodes a P450 enzyme involved in O-deethylation of phenacetin. It is 1 of several forms of cytochrome P-450 that have been purified to electrophoretic homogeneity from human liver microsomes (Guengerich et al., 1986). P1-450 (CYP1A1; 108330) and P3-450 are 2 members of the dioxin-inducible P450 gene family.
Jaiswal et al. (1987) isolated a cDNA corresponding to the CYP1A2 gene. The deduced 515-residue protein has a molecular mass of 583 kD. Phenacetin O-deethylase differs from another cytochrome P-450 enzyme that shows genetic polymorphism, debrisoquine 4-hydroxylase (124030), in molecular mass, amino acid composition, catalytic activity, and immunochemical properties.
Butler et al. (1989) reviewed the evidence that phenacetin O-deethylase, otherwise known as P450(PA), is the product of the CYP1A2 gene.
Ikeya et al. (1989) found that the human CYP1A2 gene spans almost 7.8 kb and contains 7 exons. The first exon is noncoding exon. Between CYP1A2 and CYP1A1, exons 2, 4, 6, and especially 5 are strikingly conserved in both nucleotides and total number of bases. The regulatory elements of the 2 genes, however, appeared to differ in location.
By somatic cell hybrid analysis, Jaiswal et al. (1987) determined that both the P3-450 and the P1-450 loci reside on human chromosome 15. In the mouse and hamster, the 2 genes are located near the equivalent of the mannosephosphate isomerase (MPI) locus (154550). The same may be true in man; MPI is located in the region 15q22-qter. The 2 CYP1 genes are within 25 kb of each other and probably are not separated by other genes (Nebert, 1988).
More than 20 clinically used drugs are partly or predominantly metabolized by CYP1A2 including caffeine, theophylline, imipramine, clozapine, and propranolol. CYP1A2 accounts for nearly 15% of the cytochrome P450 in the human liver (Shimada et al., 1994). CYP1A2 displays higher activity in men than in women, and is inhibited by oral contraceptives. Inducers of CYP1A2 include cruciferous vegetables (Vistisen et al., 1992). Cigarette smoking has also been shown to increase CYP1A2 activity (Sesardic et al., 1988).
Butler et al. (1989) reported that human hepatic microsomal caffeine 3-demethylation, the initial major step in caffeine biotransformation in humans, is selectively catalyzed by CYP1A2. The authors suggested that variation in caffeine 3-demethylation activity in humans could be used to characterize arylamine N-oxidation phenotypes, which may play a role in interindividual susceptibility to arylamine-induced cancers. For example, smokers have been demonstrated to have increased rates of caffeine disposition, with plasma half lives one-half that of nonsmokers. Furthermore, rates of caffeine metabolism vary between individuals, as caffeine half-life values ranging from 1.5 to 9.5 hours have been reported.
Shahidi (1967) described the familial occurrence of acetophenetidin susceptibility, suggesting genetic factors in the effects of CYP1A2.
Devonshire et al. (1983) demonstrated a genetic polymorphism for phenacetin O-deethylation, with 5 to 10% of the population deficient in this activity.
In human liver samples, Ikeya et al. (1989) found more than 15-fold differences in levels of CYP1A2 mRNA, and Schweikl et al. (1993) observed more than 40-fold differences. These findings indicated a genetically-determined difference in constitutive and/or inducible CYP1A2 gene expression.
Nakajima et al. (1999) and Sachse et al. (1999) reported single nucleotide polymorphisms (SNPs) in the CYP1A2 gene causing high inducibility.
Among 786 Caucasian individuals tested for caffeine clearance derived from saliva concentrations, Tantcheva-Poor et al. (1999) found that CYP1A2 activity was influenced by the amount of coffee drunk daily, smoking, and country of residence, activities being lower in Bulgaria and Slovakia than in Germany. These and other covariates studied explained 37% of overall variation. No relative polymorphism was found for CYP1A2 activity when adjusted for covariate effects.
Rasmussen et al. (2002) determined the caffeine ratio in a 6-hour urine sample from 378 Danish twin pairs following oral intake of a single dose of 200 mg of caffeine. The mean caffeine ratio was 5.9 +/- 3.4. The caffeine ratio was statistically significantly higher in men compared to women, in smoking men and women compared to nonsmoking persons of the same gender, and in women not taking oral contraceptives compared with women on oral contraceptives.
In a study of heritability, Rasmussen et al. (2002) investigated 49 monozygotic twin pairs and 34 same gender dizygotic twin pairs concordant for nonsmoking and non-use of oral contraceptives. A biometrical model for the caffeine ratio including only additive genetic factors and unique environmental factors was the overall best-fitting model. The heritability estimate based on this model was 0.725; unique environmental effects seemed to account for the remaining 0.275.
Individuals with the most common form of porphyria, porphyria cutanea tarda (PCT; 176100), are believed to be genetically predisposed to development of clinically overt disease through mutations and polymorphisms in genes associated with known precipitating factors. Christiansen et al. (2000) examined a group of Danish patients with PCT for the presence of a C/A polymorphism in intron 1 of CYP1A2. The results demonstrated that the frequency of the highly inducible A/A genotype is increased in both familial and sporadic PCT. The authors suggested that the A/A genotype is a susceptibility factor for PCT.
Wooding et al. (2002) studied SNPs in the CYP1A2 gene in 113 individuals from 3 major continental regions of the Old World (Africa, Asia, and Europe), in comparison with the sequences in the 90-member National Institutes of Health DNA Polymorphism Discovery Resource. The African population had the highest level of nucleotide diversity, the lowest level of linkage disequilibrium, and 2 distinct haplotype clusters with broadly overlapping geographic distributions. Haplotypes found outside of Africa were mostly a subset of those found within Africa. These patterns were all consistent with the African origin of modern humans.
Browning et al. (2010) sequenced the CYP1A2 gene from buccal swab DNA samples from 381 adults nearly equally divided between 5 Ethiopian ethnic groups representing an approximate northeast-to-southwest transect across the country. They identified 49 different variable sites, including 9 nonsynonymous changes, 7 of which were novel, and 1 synonymous change, and 55 different haplotypes, 52 of which were novel. None of the variant sites occurred near intron/exon boundaries, and all reported catalytic residues (i.e., asp320 and thr321 in exon 4 and phe451 and cys458 in exon 7) were monomorphic. Most individuals had at least 1 copy of the ancestral haplotype. However, Ethiopian groups displayed twice the variation seen in all other population groups combined. Browning et al. (2010) concluded that, consistent with the hypothesis of Africa, in general, and Ethiopia, in particular, being the birthplace of mankind, genetic diversity is greater in this population and that this diversity has significant implications for health care interventions in terms of increased risk of adverse drug reactions.
In mice, Buters et al. (1996) showed that the clearance of caffeine is determined primarily by Cyp1a2.
CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines. To define better the developmental and metabolic functions of this enzyme, Liang et al. (1996) developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells. Mice homozygous for the targeted Cyp1a2 gene were completely viable and fertile; histologic examination of 15-day embryos, newborn pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appeared unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate for CYP1A2, they studied the knockout animals by using the zoxazolamine test. The knockout mice exhibited dramatically lengthened paralysis times relative to wildtype mice and the heterozygotes showed an intermediate effect.
Paolini et al. (1999) found significant increases in the carcinogen-metabolizing enzymes CYP1A1, CYP1A2, CYP3A (124010), CYP2B (123930), and CYP2A (see 122720) in the lungs of rats supplemented with high doses of beta-carotene. The authors suggested that correspondingly high levels of CYPs in humans would predispose an individual to cancer risk from the widely bioactivated tobacco-smoke procarcinogens, thus explaining the cocarcinogenic effect of beta-carotene in smokers.
Browning, S. L., Tarekegn, A., Bekele, E., Bradman, N., Thomas, M. G. CYP1A2 is more variable than previously thought: a genomic biography of the gene behind the human drug-metabolizing enzyme. Pharmacogenet. Genomics 20: 647-664, 2010. [PubMed: 20881513] [Full Text: https://doi.org/10.1097/FPC.0b013e32833e90eb]
Buters, J. T. M., Tang, B.-K., Pineau, T., Gelboin, H. V., Kimura, S., Gonzalez, F. J. Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2. Pharmacogenetics 6: 291-296, 1996. [PubMed: 8873215] [Full Text: https://doi.org/10.1097/00008571-199608000-00002]
Butler, M. A., Iwasaki, M., Guengerich, F. P., Kadlubar, F. F. Human cytochrome P-450(PA) (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc. Nat. Acad. Sci. 86: 7696-7700, 1989. [PubMed: 2813353] [Full Text: https://doi.org/10.1073/pnas.86.20.7696]
Christiansen, L., Bygum, A., Jensen, A., Thomsen, K., Brandrup, F., Horder, M., Petersen, N. E. Association between CYP1A2 polymorphism and susceptibility to porphyria cutanea tarda. Hum. Genet. 107: 612-614, 2000. [PubMed: 11153915] [Full Text: https://doi.org/10.1007/s004390000415]
Devonshire, H. W., Kong, I., Cooper, M., Sloan, T. P., Idle, J. R., Smith, R. L. The contribution of genetically determined oxidation status to inter-individual variation in phenacetin disposition. Brit. J. Clin. Pharm. 16: 157-166, 1983. [PubMed: 6615690] [Full Text: https://doi.org/10.1111/j.1365-2125.1983.tb04980.x]
Guengerich, F. P., Distlerath, L. M., Reilly, P. E. B., Wolff, T., Shimada, T., Umbenhauer, D. R., Martin, M. V. Human-liver cytochromes P-450 involved in polymorphisms of drug oxidation. Xenobiotica 16: 367-378, 1986. [PubMed: 3739363] [Full Text: https://doi.org/10.3109/00498258609050245]
Ikeya, K., Jaiswal, A. K., Owens, R. A., Jones, J. E., Nebert, D. W., Kimura, S. Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression. Molec. Endocr. 3: 1399-1408, 1989. [PubMed: 2575218] [Full Text: https://doi.org/10.1210/mend-3-9-1399]
Jaiswal, A. K., Nebert, D. W., McBride, O. W., Gonzalez, F. J. Human P(3)450: cDNA and complete protein sequence, repetitive Alu sequences in the 3-prime nontranslated region, and localization of gene to chromosome 15. J. Exp. Path. 3: 1-17, 1987.
Liang, H.-C. L., Li, H., McKinnon, R. A., Duffy, J. J., Potter, S. S., Puga, A., Nebert, D. W. Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc. Nat. Acad. Sci. 93: 1671-1676, 1996. [PubMed: 8643688] [Full Text: https://doi.org/10.1073/pnas.93.4.1671]
Nakajima, M., Yokoi, T., Mizutani, M., Kinoshita, M., Funayama, M., Kamataki, T. Genetic polymorphism in the 5-prime-flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans. J. Biochem. 125: 803-808, 1999. [PubMed: 10101295] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a022352]
Nebert, D. W. Personal Communication. Bethesda, Md. 2/3/1988.
Paolini, M., Cantelli-Forti, G., Perocco, P., Pedulli, G. F., Abdel-Rahman, S. Z., Legator, M. S. Co-carcinogenic effect of beta-carotene. (Letter) Nature 398: 760-761, 1999. [PubMed: 10235258] [Full Text: https://doi.org/10.1038/19655]
Rasmussen, B. B., Brix, T. H., Kyvik, K. O., Brosen, K. The interindividual differences in the 3-demthylation (sic) of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics 12: 473-478, 2002. [PubMed: 12172216] [Full Text: https://doi.org/10.1097/00008571-200208000-00008]
Sachse, C., Brockmoller, J., Bauer, S., Roots, I. Functional significance of a C-to-A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Brit. J. Clin. Pharm. 47: 445-449, 1999. [PubMed: 10233211] [Full Text: https://doi.org/10.1046/j.1365-2125.1999.00898.x]
Schweikl, H., Taylor, J. A., Kitareewan, S., Linko, P., Nagorney, D., Goldstein, J. A. Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 3: 239-249, 1993. [PubMed: 8287062] [Full Text: https://doi.org/10.1097/00008571-199310000-00003]
Sesardic, D., Boobis, A. R., Edwards, R. J., Davies, D. S. A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking. Brit. J. Clin. Pharm. 26: 363-372, 1988. [PubMed: 3190986] [Full Text: https://doi.org/10.1111/j.1365-2125.1988.tb03393.x]
Shahidi, N. T. Acetophenetidin sensitivity. Am. J. Dis. Child. 113: 81-82, 1967. [PubMed: 6015912] [Full Text: https://doi.org/10.1001/archpedi.1967.02090160131017]
Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., Guengerich, F. P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharm. Exp. Ther. 270: 414-423, 1994. [PubMed: 8035341]
Tantcheva-Poor, I., Zaigler, M., Rietbrock, S., Fuhr, U. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics 9: 131-144, 1999. Note: Erratum: Pharmacogenetics 9: 781 only, 1999. [PubMed: 10376760]
Vistisen, K., Poulsen, H. E., Loft, S. Foreign compound metabolism capacity in man measured from metabolites of dietary caffeine. Carcinogenesis 13: 1561-1568, 1992. [PubMed: 1394840] [Full Text: https://doi.org/10.1093/carcin/13.9.1561]
Wooding, S. P., Watkins, W. S., Bamshad, M. J., Dunn, D. M., Weiss, R. B., Jorde, L. B. DNA sequence variation in a 3.7-kb noncoding sequence 5-prime of the CYP1A2 gene: implications for human population history and natural selection. Am. J. Hum. Genet. 71: 528-542, 2002. [PubMed: 12181774] [Full Text: https://doi.org/10.1086/342260]