Mouse livers perfused in situ with the pesticide methyl parathion (O,O-dimethyl O-P-nitrophenyl phosphorothioate) resulted in the appearance of the toxic metabolite, methyl paraoxon (O,O-dimethyl-O-P-nitrophenyl phosphate), in the effluent perfusate. Mouse whole blood rapidly detoxified methyl paraoxon in vitro, but not at a rate sufficient to prevent transport of at least some of this toxic metabolite from liver to other tissues in vivo. The hepatic disposition and biotransformation of methyl parathion in perfused livers were altered markedly by changes in protein binding of methyl parathion to perfusate, but only slightly by changes in perfusate flow rates that maintained viable livers. Pretreatment of mice with phenobarbital daily for 4 days (80 mg/kg, ip) induced hepatic microsomal activation of methyl parathion to methyl paraoxon in vitro and increased the clearance of methyl parathion by perfused mouse livers. However, in contrast to perfusion of methyl parathion into livers from saline-pretreated mice, perfusion of methyl parathion into livers from phenobarbital-pretreated mice did not lead to the appearance of methyl paraoxon in effluent perfusate. Nevertheless, methyl paraoxon was produced intrahepatically during these perfusions since hepatic cholinesterase activities were depressed compared to livers from phenobarbital-pretreated mice perfused without methyl parathion. Furthermore, phenobarbital pretreatment antagonized the acute toxicity of methyl parathion in vivo in the mouse. These data demonstrate that the net result of the biotransformation of methyl parathion by livers in untreated mice is metabolic activation, whereas the net result by livers of phenobarbital-pretreated mice is detoxification. The enhanced detoxification of methyl parathion following phenobarbital pretreatment probably accounts for, at least in part, the antagonism of methyl parathion toxicity observed following phenobarbital pretreatment.
|Original language||English (US)|
|Number of pages||5|
|Journal||Drug Metabolism and Disposition|
|State||Published - 1987|
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science