Freedland Julian, Cera Cinzia, Fasullo Michael
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.
Mutat Res Genet Toxicol Environ Mutagen. 2017 Mar;815:35-43. doi: 10.1016/j.mrgentox.2017.02.002. Epub 2017 Feb 20.
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 (AFB), 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.
细胞色素P450 1A1（CYP1A1）具有对外源生物活性物质进行解毒的功能，但偶尔也会将化合物转化为强效基因毒素。CYP1A1可激活多环芳烃，如苯并[a]芘7,8 - 二氢二醇（BaP - DHD），使其具有基因毒性。CYP1A1的特定等位基因，如CYP1A1 I462V，与乳腺癌和肺癌的较高发病率相关，但尚不清楚这些变体在体内表达的酶是否在产生基因毒素方面更具效力。我们在酿酒酵母（芽殖酵母）的野生型和DNA修复缺陷突变株中分别表达了CYP1A1（CYP1A1.1）、CYP1A1 T461N（CYP1A1.4）和I462V（CYP1A1.2）等位基因，并研究了在暴露于BaP - DHD、黄曲霉毒素B1（AFB）和杂环芳香胺（HAAs）后，哪些酵母菌株表现出与致癌物相关的最高水平的基因毒性。我们在一种同时缺乏核苷酸切除修复和重组修复的DNA修复突变体中测量了与致癌物相关的重组、Rad51焦点以及与致癌物相关的毒性。通过测量乙氧异吩唑酮 - O - 脱乙基酶（EROD）活性来确认CYP1A1的活性。我们的数据表明，与CYP1A1相比，CYP1A1 I462V等位基因赋予的与致癌物相关的基因毒性最小；然而，结果因化学致癌物和基因毒性终点而异。我们推测，CYP1A1 I462V与癌症相关的风险可能是由接触其他外源生物活性物质引起的。
