Toxicological implications of the mixed-function oxidase catalyzed metabolism of carbon disulfide.
The results of these studies have indicated that the decrease in the activity of the hepatic mixed-function oxidase enzyme system and the concentration of cytochrome P-450 seen on incubation of carbon disulfide (CS2) with rat liver microsomes in the presence of NADPH is the result of the binding of the sulfur atom released in the mixed-function oxidase catalyzed metabolism of CS2 to carbonyl sulfide (COS). Moreover, it appears that COS is further metabolized by the mixed-function oxidase enzyme system to CO2 and that, analogous to the metabolism of CS2 to COS, the sulfur atom released in this reaction also binds to the microsomes and inhibits benzphetamine metabolism and decreases the concentration of cytochrome P-450 detectable as its carbon monoxide complex. The results of these studies also suggest that the decrease in the concentration of cytochrome P-450 and the liver damage seen on in vivo administration of CS2 to phenobarbital pretreated rats, is due to the mixed-function oxidase catalyzed release and binding of the sulfur atoms of CS2. The decrease in the concentration of cytochrome P-450 seen on incubation of CS2 with rat liver microsomes in the presence of NADPH  does not appear to be the result of destruction of the heme group or its dissociation from the apoenzyme since the total amount of protoheme is unchanged in microsomes which have been incubated with CS2 and NADPH as compared to those not incubated with these compounds.
D000818:Animals; D001589:Benzphetamine; D002246:Carbon Disulfide / Q000378:metabolism* / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009249:NADP / Q000494:pharmacology; D010088:Oxidoreductases; D011335:Proadifen / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D013461:Sulfur Oxides / Q000378:metabolism / Q000494:pharmacology; D013462:Sulfur Radioisotopes
D013461:Sulfur Oxides; D013462:Sulfur Radioisotopes; D001589:Benzphetamine; D006418:Heme; D008315:Malondialdehyde; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D002246:Carbon Disulfide