Glutathione and hepatic mixed-function oxidase activity.
It is apparent that hepatic GSH may function in drug metabolism not only as a substrate for conjugation but also in regulation of cytochrome P-450 activity. The remarkable aspect of the latter activity is its specificity. Loss of hepatic GSH depresses N-demethylation of DAB while ring hydroxylation is unaffected. On the other hand, the effect is to some degree nonspecific in that control as well as PB- or MC-induced N-demethylation is inhibited. Thus the response may not simply be specific to one isozyme of cytochrome P-450 but may be associated with one aspect of the enzymic activity of several cytochrome P-450 isozymes (i.e., N-demethylation). We have postulated that sensitivity of this activity to lipid peroxidation underlies the relationship to GSH since the tripeptide serves as a major protection against hepatic lipid peroxidation and its consequences. It is as yet not clear as to how or why this particular aspect of P-450 activity is more sensitive to lipid peroxidation than are other activities such as ring hydroxylation. Ongoing investigations include attempts to identify the cytochrome P-450 isozyme(s) which inhibit this response to GSH depletion. GSH-lipid peroxidation relationships have already been reported with isolated hepatocytes, and there may be a possible connection between this and the relative instability of cytochrome P-450 in cultured hepatocytes. Another factor which may be involved is heme oxygenase activity, which is markedly induced in the liver after GSH depletion, after cobalt administration (which also depresses cytochrome P-450 activity), and during incubation of isolated hepatocytes. This enzyme catalyzes the rate-limiting step in heme breakdown and may contribute to the loss of cytochrome P-450 activity associated with GSH depletion.
D000818:Animals; D001646:Bile / Q000378:metabolism; D005557:Formaldehyde / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D004124:p-Dimethylaminoazobenzene / Q000378:metabolism
D007659:Ketones; D008054:Lipid Peroxides; D005557:Formaldehyde; C018637:phorone; D004124:p-Dimethylaminoazobenzene; D006899:Mixed Function Oxygenases; D005979:Glutathione Peroxidase; D005978:Glutathione