Carcinogenesis, Vol. 22, No. 3, 453-459,
March 2001
© 2001 Oxford University Press
CARCINOGENESIS |
Differential metabolism of benzo[a]pyrene and benzo[a]pyrene-7,8-dihydrodiol by human CYP1A1 variants
Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, D-10098 Berlin, Germany,
1 Institute of Bioorganic Chemistry, Academy of Sciences Belarus, 220141 Minsk, Belarus, and
2 Max Delbrueck Center for Molecular Medicine, D-13125 Berlin-Buch, Germany
Cytochrome P450 1A1 (CYP1A1) plays a key role in the metabolism of carcinogens, such as benzo[a]pyrene (B[a]P) and metabolites to ultimate carcinogens. Three human allelic variants, namely wild-type (CYP1A1.1), CYP1A1.2 (I462V) and CYP1A1.4 (T461N), were coexpressed by coinfection of baculovirus-infected insect cells with human NADPH-P450 reductase. These recombinant enzymes (in microsomal membranes) were used to analyze whether CYP1A1 polymorphisms affect catalytic activities towards B[a]P and B[a]P-7,8-dihydrodiol. The complete spectrum of phase I metabolites, including the tetrahydrotetrols resulting from hydrolysis of the ultimate carcinogen, B[a]P-7,8-dihydrodiol-9,10-epoxide, was examined by HPLC. Wild-type enzyme showed the highest total metabolism of B[a]P, CYP1A1.2 was ~50%, and CYP1A1.4 ~70%. Km values for all metabolites with CYP1A1.2 were generally significantly lower than with wild-type enzyme (e.g. B[a]P-7,8-diol formation: 13.8 µM for wild-type, 3.5 µM for CYP1A1.2 and 7.7 µM for CYP1A1.4). Addition of epoxide hydrolase markedly increases the relative diol-to-phenol activities by all three variants. However, CYP1A1.4 exhibits the greatest efficiency to produce diol species. Each variant produced the diol epoxides from B[a]P-7,8-dihydrodiol. CYP1A1.1 exhibited with 10.4 pmol/min/pmol CYP1A1 the greatest total rate for 7,8-diol metabolites followed by CYP1A1.2 (7.2 pmol/min/pmol CYP1A1) and CYP1A1.4 (5.5 pmol/min/pmol CYP1A1). All enzyme variants produced about three times more diol epoxide 2-derived metabolites than diol epoxide 1-derived ones, whereby both rare allelic variants exhibited statistically significantly increased formation of diol epoxide 2. This study showed that the three CYP1A1 variants had different enzyme kinetics properties to produce both the diol metabolites from B[a]P and the ultimate mutagenic species diol epoxide 2 from B[a]P-7,8-dihydrodiol, which must be considered in the evaluation of individual susceptibility to cancer.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. L. Goode, J. D. Potter, W. R. Bamlet, D. N. Rider, and J. Bigler Inherited variation in carcinogen-metabolizing enzymes and risk of colorectal polyps Carcinogenesis, February 1, 2007; 28(2): 328 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Hecht, S. G. Carmella, A. Yoder, M. Chen, Z.-z. Li, C. Le, R. Dayton, J. Jensen, and D. K. Hatsukami Comparison of polymorphisms in genes involved in polycyclic aromatic hydrocarbon metabolism with urinary phenanthrene metabolite ratios in smokers. Cancer Epidemiol. Biomarkers Prev., October 1, 2006; 15(10): 1805 - 1811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-K. Leung, K.-M. Lau, J. Mobley, Z. Jiang, and S.-M. Ho Overexpression of Cytochrome P450 1A1 and Its Novel Spliced Variant in Ovarian Cancer Cells: Alternative Subcellular Enzyme Compartmentation May Contribute to Carcinogenesis Cancer Res., May 1, 2005; 65(9): 3726 - 3734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kisselev, W.-H. Schunck, I. Roots, and D. Schwarz Association of CYP1A1 Polymorphisms with Differential Metabolic Activation of 17{beta}-Estradiol and Estrone Cancer Res., April 1, 2005; 65(7): 2972 - 2978. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Doherty, N. S. Weiss, R. J. Freeman, D. A. Dightman, P. J. Thornton, J. R. Houck, L. F. Voigt, M. A. Rossing, S. M. Schwartz, and C. Chen Genetic Factors in Catechol Estrogen Metabolism in Relation to the Risk of Endometrial Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2005; 14(2): 357 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, J. P. Wise, T. R. Holford, H. Xie, P. Boyle, S. H. Zahm, J. Rusiecki, K. Zou, B. Zhang, Y. Zhu, et al. Serum Polychlorinated Biphenyls, Cytochrome P-450 1A1 Polymorphisms, and Risk of Breast Cancer in Connecticut Women Am. J. Epidemiol., December 15, 2004; 160(12): 1177 - 1183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Schwarz, P. Kisselev, and I. Roots St. John's Wort Extracts and Some of Their Constituents Potently Inhibit Ultimate Carcinogen Formation from Benzo[a]pyrene-7,8-Dihydrodiol by Human CYP1A1 Cancer Res., November 15, 2003; 63(22): 8062 - 8068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Hung, P. Boffetta, J. Brockmoller, D. Butkiewicz, I. Cascorbi, M. L. Clapper, S. Garte, A. Haugen, A. Hirvonen, S. Anttila, et al. CYP1A1 and GSTM1 genetic polymorphisms and lung cancer risk in Caucasian non-smokers: a pooled analysis Carcinogenesis, May 1, 2003; 24(5): 875 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Laden, N. Ishibe, S. E. Hankinson, M. S. Wolff, D. M. Gertig, D. J. Hunter, and K. T. Kelsey Polychlorinated Biphenyls, Cytochrome P450 1A1, and Breast Cancer Risk in the Nurses' Health Study Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1560 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Alexandrov, I. Cascorbi, M. Rojas, G. Bouvier, E. Kriek, and H. Bartsch CYP1A1 and GSTM1 genotypes affect benzo[a]pyrene DNA adducts in smokers' lung: comparison with aromatic/hydrophobic adduct formation Carcinogenesis, December 1, 2002; 23(12): 1969 - 1977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sachse, G. Smith, M. J.V. Wilkie, J. H. Barrett, R. Waxman, F. Sullivan, D. Forman, D. T. Bishop, and C.R. Wolf A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer Carcinogenesis, November 1, 2002; 23(11): 1839 - 1850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lauterbach, E. Barbosa-Sicard, M.-H. Wang, H. Honeck, E. Kargel, J. Theuer, M. L. Schwartzman, H. Haller, F. C. Luft, M. Gollasch, et al. Cytochrome P450-Dependent Eicosapentaenoic Acid Metabolites Are Novel BK Channel Activators Hypertension, February 1, 2002; 39(2): 609 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Basham, P. D.P. Pharoah, Catherine.S. Healey, R. N. Luben, N. E. Day, D. F. Easton, B. A.J. Ponder, and A. M. Dunning Polymorphisms in CYP1A1 and smoking: no association with breast cancer risk Carcinogenesis, November 1, 2001; 22(11): 1797 - 1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. B. J. Smith, P. A. Harper, J. M. Y. Wong, M. S. M. Lam, K. R. Reid, D. Petsikas, and T. E. Massey Human Lung Microsomal Cytochrome P4501A1 (CYP1A1) Activities: Impact of Smoking Status and CYP1A1, Aryl Hydrocarbon Receptor, and Glutathione S-Transferase M1 Genetic Polymorphisms Cancer Epidemiol. Biomarkers Prev., August 1, 2001; 10(8): 839 - 853. [Abstract] [Full Text] [PDF]
|
|