The effects of carbon disulphide on rat liver microsomal mixed-function oxidases, in vivo and in vitro.
An intraperitoneal dose of CS(2) (500mg/kg) to male rats resulted in loss of liver microsomal mixed-function-oxidase activity (85% loss of biphenyl 4-hydroxylase), followed by denaturation of liver cytochrome P-450 to cytochrome P-420, and degradative loss of both cytochromes (50% loss). Losses of NADPH-cytochrome c reductase (20%) and cytochrome b(5) were considerably less. Intraperitoneal administration of CS(2) (100mg/kg) to rats pretreated wtih phenobarbitone or 3-methylcholanthrene resulted in similar losses, but the rate of destruction was greater with cytochrome P-450 than with cytochrome P-448. At 12h after intraperitoneal injection of CS(2) to non-pretreated rats, a new cytochrome (P-448) appeared. Rat liver microsomal preparations incubated with CS(2) in the presence of NADPH and O(2) resulted in loss of cytochrome P-450 and mixed-function-oxidase activity directly related to the concentration of CS(2) (10-100mum) and to the period of incubation. Addition of EDTA (1mm) completely inhibited this destruction of cytochrome P-450 by CS(2)in vitro. Addition of CS(2) to liver microsomal preparations resulted in moderate increases in the K(s) values for type-I or type-II substrates, but these were insufficient to account for the inhibition of the mixed-function oxidases. We therefore suggest that desulphuration of CS(2) leads to binding of the S to cytochrome P-450, denaturation of cytochrome P-450 to cytochrome P-420, and ultimately to destruction of these cytochromes by autoxidation.
D000818:Animals; D002246:Carbon Disulfide / Q000494:pharmacology*; D055598:Chemical Phenomena; D002621:Chemistry; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D013217:Starvation / Q000201:enzymology
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D002246:Carbon Disulfide