Diethylthiophosphate and diethyldithiophosphate induce genotoxicity in hepatic cell lines when activated by further biotransformation via Cytochrome P450

Abstract

Organophosphorous (OP) compounds are the most commonly used pesticides. There are several published reports on the direct toxicity of OP pesticides, but few data on the toxicity of their metabolites. To determine if diethylthiophosphate (DETP) and diethyldithiophosphate (DEDTP), two of the major OP metabolites, demonstrate genotoxicity, and to elucidate the possible genotoxic mechanisms, we treated WRL68, HepG2, HeLa and human blood cells with different concentrations of DETP and DEDTP. We evaluated the possible contribution of oxidative stress generation and P450 enzymes to the genotoxicity of the OP metabolites, as determined using the comet assay. Our results showed that both OP metabolites (DETP and DEDTP) induce DNA damage only in the hepatic cell lines, and this effect could be related to a secondary non-diffusible metabolite generated by the activity of P450 enzymes since P450 enzyme inhibitors also inhibited the induction of DNA damage in hepatic cells. These secondary metabolites should be taken into account when assessing risk to human populations exposed to OP pesticides.