Genotoxicity of 1-methylpyrene and 1-hydroxymethylpyrene in Chinese hamster V79-derived cells expressing both human CYP2E1 and SULT1A1
1-Methylpyrene is a widespread pollutant that is carcinogenic in animals following metabolic activation.Previous studies have shown that benzylic hydroxylation of 1-methylpyrene, catalyzed by multiple CYP isoforms, gives rise to 1-hydroxymethylpyrene, which becomes bio-reactive following further metabolism by various sulfotransferase (SULT) isoforms.However, the mutagenic and chromosome damaging effects of 1-methylpyrene and 1-hydroxymethylpyrene in mammalian cells have not been investigated.In this study a Chinese hamster V79-derived cell line expressing both human CYP2E1 and human SULT1A1 was used to investigate the ability of 1-methylpyrene and 1-hydroxymethylpyrene to induce cytotoxicity (using the CCK-8 assay), micronuclei and Hprt gene mutations.The role of each enzyme was investigated through co-exposure in the presence of an enzyme inhibitor.We found that at concentrations of 0.5-4 μM and 5-20 μM, under conditions where no reduction in cell viability/growth occurred, 1-hydroxymethylpyrene and 1-methylpyrene induced micronuclei in V79-hCYP2El-hSULT1A1 cells in a concentration-dependent manner;however, both compounds were inactive in V79 cells.Similarly, they both caused an increase in Hprt mutant frequency in V79-hCYP2El-hSULT1A1 cells in these concentration ranges, with 1-methylpyrene impairing cell viability/growth at 10 μM and above in the mutagenicity assay.The compounds were again both inactive in V79 cells.The effects of 1-hydroxymethylpyrene in V79-hCYP2El-hSULT1A1 cells were blocked or reduced by addition of pentachlorophenol, a SULT1 inhibitor;the genotoxicity of 1-methylpyrene was significantly reduced by either 1-aminobenotrazole, a CYP2E1 inhibitor, or pentachlorophenol.The results suggest that human CYP2E1 and SULT1A1 cooperate to activate 1-methylpyrene and cause genotoxicity in mammalian cells.
CYP2E1 genetically engineered cells 1-methylpyrene genotoxicity sulfotransferase (SULT) 1A1
Keqi Hu Hao Jiang Yanmei Lai Yungang Liu
Department of Toxicology, School of Public Health and Tropical Medicine, Southern Medical University, 1023 S.Shatai Road, Guangzhou 510515, China
国内会议
中国毒理学会生化与分子毒理专业委员会学术会议暨环境内分泌干扰物的毒理学研究新技术新方法研讨会
深圳
英文
71-80
2014-10-28（万方平台首次上网日期，不代表论文的发表时间）