Fipronil, a highly active and broad spectrum insecticide from the phenyl pyrazole family, is a potent disruptor of the ?-aminobutyric acid (GABA)-gated chloride channel in the insect central nervous system. It owes its insect selectivity to the fact that it is less potent in binding the GABA receptor in mammals. Since its discovery about a decade ago, fipronil has been used against a variety of agricultural, domestic and veterinary insect pests. Despite its wide range of use, however, mammalian metabolism of fipronil has not been extensively investigated. The human metabolism of fipronil has been studied in our laboratory using human liver microsomes (HLM) and cytochrome P450 (CYP) isoforms. CYP3A4 has been identified as the major enzyme catalyzing fipronil metabolism in human. Because of broad substrate specificity of CYP3A4, fipronil may interact with many other CYP3A4 substrates. This study investigated metabolic interactions of fipronil with testosterone or diazepam, two other CYP3A4 substrates. Fipronil was incubated with testosterone or diazepam in HLM and metabolites were analyzed using HPLC. When 1.25, 5 or 20 ?M fipronil incubated with a serial concentrations of testosterone (0-200 ?M), activation of fipronil S-oxidation was observed using HLM as the enzyme source. Inhibition of testosterone 6?-hydroxylation was observed in HLM when incubating testosterone (4, 20, or 100 ?M) with fipronil (0-160 ?M). There were no significant effects of diazepam (0-400 ?M) on metabolism of fipronil (5, 20 or 80 ?M). However, when 6.25, 25 or 100 ?M concentrations of diazepam were incubated with fipronil (0-160 ?M), diazepam hydroxylation was not significantly affected although demethylation of diazepam was inhibited. These results demonstrate that fipronil has the potential to interact with other CYP3A4 substrates
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