The effects of phenobarbital pretreatment on the metabolism and acute toxicity of the pesticide parathion in the mouse.
Single-pass perfusion of mouse livers in situ with the phosphorothioate pesticide parathion resulted in formation of the cholinesterase inhibitor paraoxon (PO), p-nitrophenol (PNP), p-nitrophenyl sulfate (PNPS), and p-nitrophenyl glucuronide (PNPG). Daily pretreatment of mice with phenobarbital (80 mg/kg, ip) for 4 days induced hepatic cytochrome P-450 content, as well as oxidative activation and oxidative detoxification of parathion, as measured in vitro. However, phenobarbital pretreatment did not alter production of PO from parathion in mouse livers perfused in situ, although it increased production of PNP, PNPS, and PNPG. Additionally, phenobarbital pretreatment antagonized the acute toxicity of parathion in mice. These results indicate that phenobarbital pretreatment clearly induces that form(s) of cytochrome P-450 catalyzing conversion of parathion to PO. Yet increased amounts of PO do not exit perfused livers from phenobarbital pretreated mice. Instead, the enhanced detoxification of parathion to PNP, PNPS, and PNPG likely results in the observed antagonism of parathion's acute toxicity.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004789:Enzyme Activation; D007700:Kinetics; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010278:Parathion / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000627:therapeutic use*
D010278:Parathion; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital