Carcinogenesis Advance Access published online on June 5, 2003
Carcinogenesis, doi:10.1093/carcin/bgg088
© 2003 by Oxford University Press
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CARCINOGENESIS
1 Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. Baltimore MD, 21205
* Corresponding author. E-mail: tsutter{at}memphis.edu.
Received 20 January 2003
; revised 23 April 2003
; accepted 4 May 2003
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 mis-sense 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 to 12% of normal activity when assayed in vitro using an S. cerevisiae microsomal expression system. A 10 base-pair deletion mutation produced no detectible 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 two-fold lower than Arg48, Ala119, Val432, Ser453 (RAVN): 1.4±0.3 and 1.3±0.4 µM respectively, compared to 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.
Single amino acid mutations, but not common polymorphisms, decrease the activity of CYP1B1 against (-)benzo[a]pyrene-7R-trans-7,8-dihydrodiol
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 Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. Baltimore MD, 21205; W. Harry Feinstone Center for Genomics Research, University of Memphis, Memphis TN, 38152
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