The role of hepatic biotransformation in mediating the acute toxicity of the phosphorothionate insecticide chlorpyrifos

The apparent (app) K m and app V max for mouse hepatic microsomal oxidative detoxification of chlorpyrifos to 3,5,6-tricholoro-2-pyridinol were 16.10 ± 6.8 μ m and 263.2 ± 22.5 nmol/liver/min, respectively. The app K m and app V max for the osidative activation of chlorpyrifos to chlorpyrifos oxon were 20.0 ± 6.5 μ m and 126.1 ± 14.6 nmol/liver/min, respectively, whereas the app K m and app V max for hepatic microsomal hydrolysis of chlorpyrifos oxon to 3,5,6-trichloro-2-pyridinol were 1.87 ± 0.36 m m and 89,450.7 ± 12,087.3 nmol/liver/min, respectively. Under first-order conditions the capacity of mouse hepatic microsomes to detoxify chlorpyrifos oxon exceeded their capacity to generate this potent cholinesterase inhibitor from chlorpyrifos by a factor of 7.6. Pretreatment of mice with phenobarbital (70 mg/kg daily for 4 days) resulted in a 2.5-fold increase in the app V max's for oxidative activation and detoxification of chlorpyrifos, and a 1.6-fold increase in the app V max for hydrolysis of chlorpyrifos oxon. The app K m 's were not altered by phenobarbital pretreatment. Administration of β-naphthoflavone (80 mg/kg/daily for 2 days) to mice resulted in a slight decrease in the app V max's for oxidative activation and detoxification of chlorpyrifos, without altering the app K m 's of the same reactions, or the hydrolysis of chlorpyrifos oxon. Phenobarbital and β-naphthoflavone increased and decreased, respectively, the predicted hepatic clearance of chlorpyrifos. The acute toxicity of chlorpyrifos was slightly antagonized by phenobarbital pretreatment, but was potentiated by β-naphthoflavone administration. These pretreatments did not affect cholinesterase, nonspecific esterase, or plasma A-esterase activities. Collectively, these results suggest that chlorpyrifos oxon formed within the liver does not escape hydrolysis by the liver, and that extrahepatic sites of activation are important in directly mediating the acute toxicity of chlorpyrifos.