Studies on the metabolism of the pneumotoxin O,S,S-trimethyl phosphorodithioate--II. Lung and liver slices.
The metabolism of O,S,S-trimethyl phosphorodithioate (OSSMe), a pneumotoxic impurity in some organophosphorus insecticides, was investigated by incubating rat lung and liver slices with 1 mM OSSMe, labelled with 3H or 14C on one of its thiolo-methyl (CH3S-) groups. Protein bound radioactivity was higher in lung slices than in liver slices. In lung slices the predominant diester produced was O,S-dimethyl phosphorothioate (OSMeO-), whereas in liver slices it was S,S-dimethyl phosphorodithioate (SSMeO-). Other studies had shown binding of radioactivity and OSMeO- production to be cytochrome P-450-dependent processes in microsomes and SSMeO- production to result from the action of cytosolic glutathione-S-transferase on OSSMe. Preincubation of slices with 10(-5) M paraoxon did not influence the amount of protein-bound radioactivity, suggesting that binding of radioactivity did not simply result from protein phosphorylation. Pretreatments of the rats with O,O,O-trimethyl phosphorothioate [OOOMe(S) 0.5, 2.5 and 12.5 mg/kg p.o.], with p-xylene (1 g/kg, i.p.) or with bromophos (5.3 mg/kg, i.p.) which all protect against the lung toxicity of OSSMe probably by inhibiting pulmonary mixed-function oxidase, also led to significant decreases in both protein binding of radioactivity and OSMeO- production in lung slices, but not in liver slices. These results show that tissue slices are a convenient system for investigating xenobiotic metabolism in the lung and they suggest that the susceptibility of the lung to OSSMe probably results from a relatively high rate of activation, coupled with a relatively low rate of metabolism by non-toxic pathways and/or removal of reactive metabolites in some lung cells, possibly the alveolar type I cells.
Nemery
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B
Medical Research Council, Toxicology Unit, Carshalton Surrey, U.K.
Aldridge
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WN
D000818:Animals; D001711:Biotransformation; D005260:Female; D005978:Glutathione / Q000502:physiology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008745:Methylation; D063086:Organothiophosphates / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000378:metabolism*; D010278:Parathion / Q000494:pharmacology; D051381:Rats; D014992:Xylenes / Q000494:pharmacology
D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; D014992:Xylenes; C033125:O,S,S-trimethyl phosphorodithioate; D010278:Parathion; C031286:4-xylene; D005978:Glutathione