Metabolic activation of the pesticide azinphos-methyl by perfused mouse livers.
Perfusion of mouse livers in situ with the phosphorodithioate pesticide azinphos-methyl (O,O-dimethyl S-[4-oxo-1,2,3-benzotriazin-3(4H)-ylmethyl] phosphorodithioate; Guthion) resulted in the appearance of the cholinesterase inhibitor azinphos-methyl oxon in effluent perfusate. Since mouse whole blood did not have the capacity to detoxify this toxic oxon rapidly enough to prevent its passage to extrahepatic tissues in vivo, the liver is likely a major source of azinphos-methyl oxon in the mouse following exposure to azinphos-methyl. Alterations in perfusate flow rates in situ had little effect on the hepatic disposition of azinphos-methyl. Conversely, significant increases in the free fraction of azinphos-methyl in perfusate led to marked changes in hepatic distribution and biotransformation of this pesticide. Phenobarbital pretreatment of mice induced hepatic cytochrome P-450 content, as well as microsomal activation of azinphos-methyl in vitro, yet antagonized the acute toxicity of this pesticide in vivo. Interestingly, perfused livers from phenobarbital-pretreated mice produced less azinphos-methyl oxon than perfused livers from saline-pretreated mice, thereby accounting for the antagonism of the acute toxicity of azinphos-methyl afforded by phenobarbital pretreatment. The mechanism of this phenobarbital-dependent decrease in appearance of azinphos-methyl oxon in effluent perfusate is unclear. However, it must be emphasized that the hepatic biotransformation of azinphos-methyl is complex, involving several sequential and simultaneous pathways, all of which could be affected by phenobarbital. The metabolic profile observed in effluent perfusate is the net result of all these pathways operating in the intact liver.
D000818:Animals; D001387:Azinphosmethyl / Q000378:metabolism*; D001711:Biotransformation; D007306:Insecticides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D010477:Perfusion; D010575:Pesticides / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D007306:Insecticides; D010575:Pesticides; D001387:Azinphosmethyl; D012710:Serum Albumin, Bovine; D010634:Phenobarbital