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Obrebska MJ, Kentish P, Parke DV: The effects of carbon disulphide on rat liver microsomal mixed-function oxidases, in vivo and in vitro. Biochem J. 1980 Apr 15;188(1):107-12.
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. |
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