Studies on the metabolism of the pneumotoxin O,S,S-trimethyl phosphorodithioate--I. Lung and liver microsomes.
The metabolism of O,S,S-trimethyl phosphorodithioate (OSSMe), a pneumotoxic impurity in some organophosphorus insecticides, was investigated in rat lung and liver microsomal preparations, using OSSMe labelled with 3H or 14C on one of its thiolo-methyl (CH3S-) groups. Production of O,S-dimethyl phosphorothioate (OSMeO-) and binding of radioactivity to protein were NADPH-dependent and were shown to be, at least partly, cytochrome P-450-dependent processes in both lung and liver microsomes. Incubation with reduced glutathione prevented the binding of radioactivity without affecting OSMeO- production. The Km for the conversion of OSSMe to OSMeO- was 15-fold lower in lung (0.30 +/- 0.07 mM) than in liver (4.63 +/- 2.42 mM) microsomes. These results show that cytochrome P-450-dependent mixed-function oxidase is implicated in at least part of the metabolic activation of OSSMe, and suggest that the pulmonary isozyme(s) are more active at metabolizing OSSMe than hepatic isozymes. It is speculated, on the basis of literature data on other sulphur-containing chemicals, that the metabolic activation of OSSMe involves oxidation of a thiolo-sulphur, with subsequent formation of CH3-S-S-protein disulphides.
Nemery
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Medical Research Council, Toxicology Unit, Carshalton, Surrey, U.K.
Aldridge
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D000818:Animals; D001711:Biotransformation; D003486:Cyanides / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D063086:Organothiophosphates / Q000378:metabolism* / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D003486:Cyanides; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; C033125:O,S,S-trimethyl phosphorodithioate; D003577:Cytochrome P-450 Enzyme System