Kanode Rewan, Chandra Saurabh, Sharma Sharad
a Drug Safety Assessment, Novel Drug Discovery & Development , Lupin Limited (Research Park) , Taluka-Mulshi , Pune , India.
Toxicol Mech Methods. 2017 Jun;27(5):376-381. doi: 10.1080/15376516.2017.1300616. Epub 2017 Mar 22.
Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, β-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, β-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens.
非遗传毒性致癌物可能在癌症发展中起重要作用。目前用于致突变性的短期试验可对遗传毒性致癌物进行分类，但缺乏检测表观遗传致癌物的能力。始终需要开发一种终点来识别使用快速实用生物测定法的潜在致癌剂。为此，本研究利用鼠伤寒沙门氏菌的TA98和TA1537测试菌株来评估四种非遗传毒性致癌剂（香豆素、β-月桂烯、邻苯二甲酸二（2-乙基己基）酯和反式茴香脑）。这些化学物质通过平板掺入法在代谢活化系统（S9）存在的情况下单独测试，并与前诱变剂2-氨基蒽（2AA）和苯并（a）芘（BP）联合测试。与单独使用前诱变剂相比，暴露于所有四种测试化学物质后，前诱变剂联合组的回复菌落明显增加。然而，与TA1537相比，TA98菌株的2AA联合组（香豆素+2AA、β-月桂烯+2AA、邻苯二甲酸二（2-乙基己基）酯+2AA和反式茴香脑+2AA）观察到显著更高的倍数反应，这似乎增强了2AA在代谢活化条件下的诱变反应。结论是，在两种测试菌株中，鼠伤寒沙门氏菌的TA98菌株在与强效前诱变剂联合使用时，有可能通过生化抑制或调节肝微粒体酶的活性来检测非遗传毒性致癌物，这可能间接导致肿瘤性改变。此外，这种简单的短期替代试验可能在推断毒理学过程中提供快速信息，以区分遗传毒性和非遗传毒性致癌物。
