title: Kinetic analyses of the microsomal biotransformation of the phosphorothioate insecticides chlorpyrifos and parathion.
abstract: 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 microM and 16.1 +/- 3.4 microM 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 microM and 26.5 +/- 3.8 microM 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.
mesh_terms: D000818:Animals; D001711:Biotransformation; D004390:Chlorpyrifos / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004492:Edetic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010278:Parathion / Q000378:metabolism*
chemical_list: D010278:Parathion; D003577:Cytochrome P-450 Enzyme System; D004492:Edetic Acid; D004390:Chlorpyrifos