Metabolic activation of the organophosphorus insecticides chlorpyrifos and fenitrothion by perfused rat liver

Abstract

The present study was undertaken to characterize the metabolic activation of the organophosphorus insecticides chlorpyrifos [O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothionate] and fenitrothion [O,O-dimethyl O-(3-methyl-p-nitrophenyl) phosphorothionate] by intact rat liver. Single-pass perfusions of rat livers with chlorpyrifos or fenitrothion to steady state conditions resulted in the appearance of their corresponding oxygen analogs in effluent. In addition, detoxification of chlorpyrifos oxon [O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphate] or fenitrooxon [O,O-dimethyl O-(3-methyl-p-nitrophenyl) phosphate] by rat blood did not proceed at a rate rapid enough to prevent passage of at least some of these chemicals from liver to extrahepatic tissues, suggesting that hepatic biotransformation of chlorpyrifos and fenitrothion by rat liver results in their net activation. Although male rat livers produced more chlorpyrifos oxon and fenitrooxon from chlorpyrifos and fenitrothion, respectively, than did livers from female rats, the acute toxicities of chlorpyrifos and fenitrothion were greater in females than in males. Therefore, differences in hepatic activation of chlorpyrifos and fenitrothion in males and females cannot account for the sex differences in their acute toxicities in the rat. Finally, S-methyl glutathione and S-p-nitrophenyl glutathione were not detected in effluent or bile of livers perfused with fenitrothion, suggesting that glutathione-mediated biotransformation of this insecticide does not occur to any significant degree in intact liver.