title: CYP1A1 I462V polymorphism is associated with reduced genotoxicity in yeast despite positive association with increased cancer risk.
abstract: CYP1A1 functions in detoxifying xenobiotics but occasionally converts compounds into potent genotoxins. CYP1A1 activates polyaromatic hydrocarbons, such as benzo[a]pyrene 7,8 dihydrodiol (BaP-DHD), rendering them genotoxic. Particular alleles of CYP1A1, such as CYP1A1 I462V have been correlated with a higher incidence of breast and lung cancer, but it is unknown whether these variants express enzymes in vivo that are more potent in generating genotoxins. We individually expressed CYP1A1 (CYP1A1.1), CYP1A1 T461N (CYP1A1.4) and I462V (CYP1A1.2) alleles in wild-type and DNA repair deficient mutant strains of Saccharomyces cerevisiae (budding yeast) and asked which yeast strains exhibited the highest levels of carcinogen-associated genotoxicity after exposure to BaP-DHD, aflatoxin B1 (AFB1), and heterocyclic aromatic amines (HAAs). We measured carcinogen-associated recombination, Rad51 foci, and carcinogen-associated toxicity in a DNA repair mutant deficient in both nucleotide excision repair and recombinational repair. CYP1A1 activity was confirmed by measuring ethoxyresorufin-O-deethylation (EROD) activities. Our data indicate that CYP1A1 I462V allele confers the least carcinogen-associated genotoxicity, compared to CYP1A1; however, results vary depending on the chemical carcinogen and the genotoxic endpoint. We speculate that the cancer-associated risk of CYP1A1 I462V may be caused by exposure to other xenobiotics.
authors.affiliation: College of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, NY 12205, United States.
authors.forename: Julian
authors.initials: J
authors.lastname: Freedland
authors.affiliation: Center for Medical Sciences,150 New Scotland Road, Albany, NY 12208, United States.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cera
authors.affiliation: College of Nanoscale Science and Engineering, State University of New York Polytechnic Institute, Albany, NY 12205, United States; Center for Medical Sciences,150 New Scotland Road, Albany, NY 12208, United States. Electronic address: mfasullo@sunypoly.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Fasullo
mesh_terms: D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
keywords: Budding yeast; CYP1A1 polymorphisms; DNA damage; Food carcinogens