Abstract
Interindividual variability of the activity of CYP1A2 may be expected to affect cancer susceptibility, since the enzyme is capable of activating several carcinogens. In the present study, we found three new polymorphisms in the 5′‐flanking region (CYP1A2/B) and intron 1 (CYP1A2/C and CYP1A2/D) of CYP1A2 in Japanese by using polymerase chain reaction‐single strand conformation polymorphism. We developed methods to detect these polymorphisms by polymerase chain reaction‐restriction fragment length polymorphism and performed a population study (159 subjects) to estimate the frequencies of the alleles. The frequencies of the CYP1A2/A (adenine), CYP1A2/B (thymine‐deleted), CYP1A2/C (guanine) and CYP1A2/D (adenine) variants were 21.1, 42.0, 8.2 and 61.3%, respectively. The results of family study supported the idea that these CYP1A2 genotypes are inherited with an autosomal codominant transmission.
Keywords: Polymorphism, PCR‐RFLP, Cytochrome P450
Full Text
The Full Text of this article is available as a PDF (83.1 KB).
REFERENCES
- 1).Butler , M. A. , Iwasaki , M. , Guengerich , F. P. and Kadlubar , F. F.Human cytochrome P‐450PA (P‐450IA2), the phenacetin O ‐deethylase, is primarily responsible for the hepatic 3‐demethylation of caffeine and N ‐oxidation of carcinogenic arylamines . Proc. Natl. Acad. Sci. USA , 86 , 7696 – 7700 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2).Kamataki , T. , Maeda , K. , Yamazoe , Y. , Matsuda , N. , Ishii , K. and Kato , R.A high‐spin form of cytochrome P‐450 highly purified from polychlorinated biphenyl‐treated rats. Catalytic characterization and immunochemical quantitation in liver microsomes . Mol. Pharmacol. , 24 , 146 – 155 ( 1983. ). [PubMed] [Google Scholar]
- 3).Yamazoe , Y. , Kamataki , T. and Kato , R.Species difference in N‐hydroxylation of a tryptophan pyrolysis product in relation to mutagenic activation . Cancer Res. , 41 , 4518 – 4522 ( 1981. ). [PubMed] [Google Scholar]
- 4).McManus , M. E. , Burgess , W. M. , Veronese , M. E. , Huggett , A. , Quattrochi , L. C. and Tukey , R. H.Metabolism of 2‐acetylaminfluorene and benzo[a]pyrene and activation of food‐derived heterocyclic amine mutagens by human cytochrome P‐450 . Cancer Res. , 50 , 3367 – 3376 ( 1990. ). [PubMed] [Google Scholar]
- 5).Butler , M. A. , Lang , N. P. , Young , J. F. , Caporaso , N. E. , Vineis , P. , Hayes , R. B. , Teitel , C. H. , Massengill , J. P. , Lawsen , M. F. and Kadlubar , F. F.Determination of CYP1A2 and NAT2 phenotypes in human populations by analysis of caffeine urinary metabolites . Pharmacogenetics , 2 , 116 – 127 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 6).Sesardic , D. , Boobis , A. R. , Edwards , R. J. and Davis , 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 . Br. J. Clin. Pharmacol. , 26 , 363 – 372 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7).Hammons , G. J. , Guengerich , F. P. , Weis , C. C. , Beland , F. A. and Kadlubar , F. F.Metabolic oxidation of carcinogenic arylamines by rat, dog, and human hepatic microsomes and by purified flavin‐containing and cytochrome P‐450 monooxygenases . Cancer Res. , 45 , 3578 – 3585 ( 1985. ). [PubMed] [Google Scholar]
- 8).Minchin , R. F. , McManus , M. E. , Boobis , A. R. , Davies , D. S. and Thorgeirsson , S. S.Polymorphic metabolism of the carcinogen 2‐acetylaminofluorene in human liver microsomes . Carcinogenesis , 6 , 1721 – 1724 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 9).Butler , M. A. , Guengrich , F. P. and Kadlubar , F. F.Metabolic oxidation of the carcinogens 4‐aminobiphenyl and 4,4′‐methylene‐bis(2‐chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P‐450 monooxygenases . Cancer Res. , 49 , 25 – 31 ( 1989. ). [PubMed] [Google Scholar]
- 10).Nakajima , M. , Yokoi , T. , Mizutani , M. , Shin , S. , Kadlubar , F. F. and Kamataki , T.Phenotyping of CYP1A2 in Japanese population by analysis of caffeine urinary metabolites: absence of mutation prescribing the phenotype in the CYP1A2 gene . Cancer Epidemiol. Biomarkers Prev. , 3 , 413 – 421 ( 1994. ). [PubMed] [Google Scholar]
- 11).Nakajima , M. , Yokoi , T. , Mizutani , M. , Kinoshita , M. , Funayama , M. and Kamataki , T.Genetic polymorphism in the 5′‐flanking region of human CYP1A2 gene: effect on the CYP1A2 inducibility in humans . J. Biochem. , 125 , 803 – 808 ( 1999. ). [DOI] [PubMed] [Google Scholar]
- 12).Sambrook , J. , Fritsch , E. E. and Maniatis , T. “ Molecular Cloning: A Laboratory Manual ” 2nd Ed. , pp . 916 – 919 ( 1989. ). Cold Spring Harbor Laboratory Press; , New York . [Google Scholar]
- 13).Quattrochi , L. C. and Tukey , R. H.The human cytochrome Cyp1A2 gene contains regulatory elements responsive to 3‐methylcholanthrene . Mol. Pharmacol. , 36 , 66 – 71 ( 1989. ). [PubMed] [Google Scholar]
- 14).Ikeya , K. , Jaiswal , A. K. , Owens , R. A. , Jones , J. E. , Nebert , D. W. and Kimura , S.Human CYP1A2: sequence, gene structure, comparison with the mouse and rat orthologous gene, and differences in liver 1A2 mRNA expression . Mol. Endocrinol. , 3 , 1399 – 1408 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 15).Sesardic , D. , Pasanen , M. , Pelkonen , O. and Boobis , A. R.Differential expression and regulation of members of the cytochrome P450IA gene subfamily in human tissues . Carcinogenesis , 11 , 1183 – 1188 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 16).Schweikl , H. , Taylor , J. A. , Kitareewan , T. S. , Linko , P. , Nagorney , D. and Goldstein , J. A.Expression of CYP1A1 and CYP1A2 genes in human liver . Pharmacogenetics , 3 , 239 – 249 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 17).Kalow , W. and Tang , B. K.Caffeine as a metabolic probe: exploration of the enzyme‐inducing effect of cigarette smoking . Clin. Pharmacol. Ther. , 49 , 44 – 48 ( 1991. ). [DOI] [PubMed] [Google Scholar]
- 18).Sachse , C. , Brockmöller , J. , Bauer , S. and Roots , I.Functional significance of a C→A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine . Br. J. Clin. Pharmacol. , 47 , 445 – 449 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]