Carcinogenesis Advance Access originally published online on June 5, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Carcinogenesis, Vol. 24, No. 7, 1247-1255,
July 2003
© 2003 Oxford University Press
CARCINOGENESIS |
Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-7,8-dihydrodiol
1 Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, Baltimore, MD 21205
2 Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, NC
3 Kleberg Cytogenetics Lab, Baylor College Medical School, Houston, TX 77030
4 W.Harry Feinstone Center for Genomics Research, University of Memphis, Memphis, TN 38152, USA
5 To whom correspondence should be addressed Email: pstrickl{at}jhsph.edu or tsutter{at}memphis.edu
Genetic differences that underlie inter-individual variation in the metabolism of common carcinogens are important potential sources of cancer susceptibility. Cytochrome P450 1B1 (CYP1B1), a central enzyme in the activation of the ubiquitous environmental carcinogen benzo[a]pyrene (B[a]P), has several genetic variants. This study investigated six rare mutations and four common polymorphisms for their effects on B[a]P metabolism. Five missense mutations associated with congenital glaucoma (Gly61Glu, Gly365Trp, Asp374Asn, Pro437Leu and Arg469Tryp) dramatically decreased the capacity of CYP1B1 to convert (-)benzo[a]pyrene-7R-trans-7,8-dihyrodiol (B[a]P-7,8-diol) to (±)benzo[a]pyrene-r-7,t-8-dihydrodiol-9,10-epoxides. These five mutations resulted in enzymes with 3–12% of normal activity when assayed in vitro using an Saccharomyces cerevisiae microsomal expression system. A 10 bp deletion mutation produced no detectable protein or activity. In contrast, proteins containing all possible combinations of four common single nucleotide polymorphisms (Arg48Gly, Ala199Ser, Val432Leu, Asn453Ser) had modest effects on B[a]P-7,8-diol metabolism. Michaelis–Menten analysis suggested that two alleles, Arg48, Ala119, Val432, Ser453 (RAVS) and Arg48, Ala119, Leu432, Ser453 (RALS), have KM values 2-fold lower than Arg48, Ala119, Val432, Ser453 (RAVN): 1.4 ± 0.3 and 1.3 ± 0.4 µM, respectively, compared with 2.8 ± 0.8 µM (P < 0.05). However, these differences could not be confirmed with direct measurements of rate at low substrate concentration. There were no significant differences for either of two other kinetic parameters, kcat or kcat/KM. Allele frequency analysis in three populations reveals the Ser453 variant is rare among those of Asian (<1%) and African ancestry (<4%), and more common in individuals of European ancestry (16%). Haplotypes containing the Ser453 variant were uncommon; only RALS was detectable in our small populations. The RALS allele occurred between 0.5% in Asians and 15% in Europeans. Our study demonstrates that rare, disease-associated mutations in CYP1B1 significantly decrease the enzyme's metabolism of B[a]P-7,8-diol; however, our results do not identify any major differences in this metabolism due to four common single amino acid polymorphisms.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Beuten, J. A.L. Gelfond, J. J. Byrne, I. Balic, A. C. Crandall, T. L. Johnson-Pais, I. M. Thompson, D. K. Price, and R. J. Leach CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians Carcinogenesis, September 1, 2008; 29(9): 1751 - 1757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Jeannot, K. Poussin, L. Chiche, Y. Bacq, N. Sturm, J.-Y. Scoazec, C. Buffet, J. T. V. Nhieu, C. Bellanne-Chantelot, C. de Toma, et al. Association of CYP1B1 Germ Line Mutations with Hepatocyte Nuclear Factor 1{alpha}-Mutated Hepatocellular Adenoma Cancer Res., March 15, 2007; 67(6): 2611 - 2616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Holt, M. A. Rossing, K. E. Malone, S. M. Schwartz, N. S. Weiss, and C. Chen Ovarian Cancer Risk and Polymorphisms Involved in Estrogen Catabolism Cancer Epidemiol. Biomarkers Prev., March 1, 2007; 16(3): 481 - 489. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Paracchini, S. Raimondi, I. T. Gram, D. Kang, N. A. Kocabas, V. N. Kristensen, D. Li, F. F. Parl, T. Rylander-Rudqvist, P. Soucek, et al. Meta- and Pooled Analyses of the Cytochrome P-450 1B1 Val432Leu Polymorphism and Breast Cancer: A HuGE-GSEC Review Am. J. Epidemiol., January 15, 2007; 165(2): 115 - 125. [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]
|
|
|
|
 |
|
 A. L. Hughes, B. Packer, R. Welch, A. W. Bergen, S. J. Chanock, and M. Yeager Effects of Natural Selection on Interpopulation Divergence at Polymorphic Sites in Human Protein-Coding Loci Genetics, July 1, 2005; 170(3): 1181 - 1187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Aklillu, S. Ovrebo, I. V. Botnen, C. Otter, and M. Ingelman-Sundberg Characterization of Common CYP1B1 Variants with Different Capacity for Benzo[a]pyrene-7,8-Dihydrodiol Epoxide Formation from Benzo[a]pyrene Cancer Res., June 15, 2005; 65(12): 5105 - 5111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Melki, E Colomb, N Lefort, A P Brezin, and H-J Garchon CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma J. Med. Genet., September 1, 2004; 41(9): 647 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Panicker, A. K. Mandal, A. B. M. Reddy, V. K. Gothwal, and S. E. Hasnain Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma Invest. Ophthalmol. Vis. Sci., April 1, 2004; 45(4): 1149 - 1156. [Abstract] [Full Text] [PDF]
|
|