Human Metabolic Interactions of Pesticides: Inhibition, Induction, and Activation

摘要

The regulation of agrochemicals utilizes, among other data, hazard determination of single chemicals carried out in surrogate animals that show little genetic variation. Relevance to real world situations is questionable, since dose and species extrapolations require uncertainty factors and agrochemicals are typically used as mixtures. Human studies provide information on population variation, sub-groups at increased risk and interactions among agrochemicals and endogenous metabolites. How components in agrochemical mixtures affect each others toxicokinetics is largely unknown. Metabolism and metabolic interactions of agrochemicals have been investigated using human hepatocytes, human liver microsomes and recombinant human cytochrome P450 (CYP) isoforms. Potential for interactions based on CYP induction, cytotoxicity, inhibition and activation is apparent. For example, in human hepatocytes fipronil is a potent inducer at low doses but cytotoxic at higher doses. The role of the pregnane X receptor (PXR) has been demonstrated in induction by pesticides and, in microarray studies of chlorpyrifos (CPS) exposed human hepatocytes, it was shown that a number of genes were differentially expressed, including gene pathways regulating detoxication enzymes, retinol metabolism, and the cytoskeleton. Phosphorothioates are potent inhibitors of the CYP metabolism of steroid hormones as well as other pesticides, including carbaryl and fipronil and some diesel fuel components. Fipronil also inhibits testosterone metabolism. Expression of CYP2B6 with age and variation in chlorpyrifos metabolism is also discussed.