CYP1A1 I462V polymorphism is associated with reduced genotoxicity in yeast despite positive association with increased cancer risk.
CYP1A1 I462V polymorphism is associated with reduced genotoxicity in yeast despite positive association with increased cancer risk.
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DOI：
10.1016/j.mrgentox.2017.02.002
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Fasullo M
中科院分区：
文献类型：
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作者：
Freedland J;Cera C;Fasullo M
CYP1A1 具有解毒异生素的功能，但偶尔也会将化合物转化为强效基因毒素。 CYP1A1 激活多芳烃，例如苯并[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（例如 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是否在体内表达更有效产生基因毒素的酶。我们在酿酒酵母（芽殖酵母）的野生型和 DNA 修复缺陷突变株中单独表达 CYP1A1 (CYP1A1.1)、CYP1A1 T461N (CYP1A1.4) 和 I462V (CYP1A1.2) 等位基因，并询问哪些酵母菌株表现出最高水平的致癌物相关遗传毒性。 接触 BaP-DHD、黄曲霉毒素 B1 (AFB1) 和杂环芳香胺 (HAAs)。我们测量了缺乏核苷酸切除修复和重组修复的 DNA 修复突变体中的致癌物相关重组、Rad51 病灶和致癌物相关毒性。通过测量乙氧基试卤灵-O-脱乙基化 (EROD) 活性证实了 CYP1A1 活性。我们的数据表明，与 CYP1A1 相比，CYP1A1 I462V 等位基因具有最小的致癌相关遗传毒性；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 的癌症相关风险可能是由暴露于其他外源性物质引起的。
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.