Effects of alkyl phosphorothioates on the hepatic microsomal mixed-function oxidase system in rats. Inhibition of drug-metabolizing enzyme activity and selective increase of NADPH-cytochrome c reductase activity.
Four series of alkyl phosphorothioates were administered to adult male rats by intraperitoneal injection, and their influences on the drug-metabolizing enzyme system in hepatic microsomes were examined. Among the alkyl phosphorothioates tested, O,O,O-trialkyl phosphorothioates (I) and O,O,S-trialkyl phosphorodithioates (II) significantly decreased hepatic microsomal cytochrome P-450 content and the metabolism of aniline and aminopyrine. Six hours after administration, triethyl compounds were the most effective of the trialkyl esters tested. In experiments on rats pretreated with phenobarbital or 3-methylcholanthrene, the inhibitory effects of triethyl esters were increased strongly by phenobarbital pretreatment and decreased by 3-methylcholanthrene. After the administration of I, a selective increase of NADPH-cytochrome c reductase activity was also observed. In the phenobarbital-pretreated rats, no further increase of NADPH-cytochrome c reductase activity was observed as a result of the administration of I. Except for the two dibutyl esters, O,O-dialkyl phosphorothioates (III) and O,O-dialkyl phosphorodithioates (IV) caused no significant inhibitory effect on the drug-metabolizing enzyme system under the same conditions. Formula: see text.
Furukawa
N
N
Sato
M
M
Suzuki
Y
Y
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis*; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D009946:Organothiophosphorus Compounds; D008748:Methylcholanthrene; D011335:Proadifen; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase; D010634:Phenobarbital