Genotoxic Assays for Measuring P450 Activation of Chemical Mutagens

Genotoxicity and Mutagenicity - Mechanisms and Test Methods Pub Date : 2019-12-12 DOI:10.5772/intechopen.90356

M. Fasullo

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Abstract

This review discusses using yeast as a model organism for studying the biological effects of P450-mediated metabolism of xenobiotics. We discuss the challenges of testing the safety of thousands of chemicals currently introduced into the market place, the limitations of the animal systems, the advantages of model organisms, and the humanization of the yeast cells by expressing human cytochrome P450 (CYP) genes. We discuss strategies in utilizing multiple genetic endpoints in screening chemicals and yeast strains that facilitate phenotyping CYP polymorphisms. In particular, we discuss yeast mutants that facilitate xenobiotic import and retention and particular DNA repair mutants that can facilitate in measuring genotoxic endpoints and elucidating genotoxic mechanisms. New directions in toxicogenetics suggest that particular DNA damaging agents may interact with chromatin and perturb gene silencing, which may also generate genetic instabilities. By introducing human CYP genes into yeast strains, new strategies can be explored for high-throughput testing of xenobiotics and identifying potent DNA damaging agents.

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测定化学诱变剂P450活化的基因毒性试验

本文就酵母作为研究p450介导的外源代谢生物学效应的模式生物进行了综述。我们讨论了测试目前进入市场的数千种化学品的安全性所面临的挑战，动物系统的局限性，模式生物的优势，以及通过表达人类细胞色素P450 (CYP)基因实现酵母细胞的人源化。我们讨论了在筛选化学品和酵母菌株中利用多个遗传端点促进表型CYP多态性的策略。我们特别讨论了促进外源输入和保留的酵母菌突变体和特定的DNA修复突变体，这些突变体可以促进测量遗传毒性终点和阐明遗传毒性机制。毒物遗传学的新方向表明，特定的DNA损伤剂可能与染色质相互作用并扰乱基因沉默，这也可能产生遗传不稳定。通过将人CYP基因导入酵母菌株，可以探索高通量检测外源药物和鉴定强效DNA损伤剂的新策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Genotoxicity and Mutagenicity - Mechanisms and Test Methods

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