Kinetic Analyses of the Microsomal Biotransformation of the Phosphorothioate Insecticides Chlorpyrifos and Parathion

Kinetic Analyses of the Microsomal Biotransformation of the Phosphorothioate Insecticides Chlorphyrifos and Parathion. Sultatos, L.G. and Murphy, S.D. (1983). Fundam. and Appl. Toxicol. 3:16-21. Chlorpyrifos [0,0-diethyl-0-(3,5,6-trichloro-2-pyridyl) phosphorothioate] was metabolized to chlorpyrifos oxon [0,0-diethyl-0-(3,5,6-trichloro-2-pyridyl) phosphate] and to 3,5,6-trichloro-2-pyridinol by mouse hepatic microsomes. Formation of both chlorpyrifos oxon and 3,5,6-trichloro-2-pyridinol required NADPH, and was inhibited by carbon monoxide. Kinetic analyses using direct linear plots determined the appKm's for formation of chlorpyrifos oxon and 3,5,6-trichloro-2-pyridinol to be 20.9 ± 3.3 μM and 16.1 ± 3.4 μM respectively, while the appVmax's for the same reactions were 3.9 ± 0.2 nmols/100 mg liver/min and 8.1 ± 0.3 nmols/100 mg liver/min respectively. Incubation of parathion [0,0-diethyl-0-(4-nitrophenyl) phosphorothioate] with mouse hepatic microsomes produced paraoxon [0,0-diethyl-0-(4-nitrophenyl) phosphate] and p-nitrophenol. The appKm's for the formation of paraoxon and p-nitrophenol were 29.6 ± 4.2 μM and 26.5 ± 3.8 μM respectively, with appVmax's of 5.8 ± 0.6 nmols/100 mg liver/min and 6.7 ± 0.5 nmols/100 mg liver/min, respectively. Incubation of both parathion and chlorpyrifos at various concentrations with mouse hepatic microsomes resulted in inhibition of production of paraoxon, p-nitrophenol, chlorpyrifos oxon, and 3,5,6-trichloro-2-pyridinol, which was characteristic of mixed type inhibition. This complex kinetic behavior could arise as a result of competitive interactions of parathion and chlorpyrifos with multiple forms of microsomal cytochrome P-450.