We have previously reported that the suicide inactivation of cytochrome P-450 by CC14 is caused by a novel pathway which involves the irreversible binding of products of the heme prosthetic group to the protein moiety of the enzyme. It was initially believed that this mechanism of enzyme inactivation was solely mediated by lipid hydroperoxides produced by carbon tetrachloride metabolites. During the last year, however, we have discovered that CC14 as well as several structurally diverse drugs and environmental chemicals can destroy cytochrome P-450 and produce heme-derived protein adducts independent of lipid hydroperoxides. This pathway appears to involve the initial reductive or oxidative metabolism of the chemical by cytochrome P-450 into a radical intermediate, which subsequently either activates the heme or protein moiety of the enzyme leading ultimately to bound heme-derived products. Not only is the enzyme irreversibly inactivated by this process, but it also appears to be """"""""tagged"""""""" for catabolism by cellular proteases. Therefore, a general pathway of chemically-induced irreversible inactivation and degradation of cytochrome P-450 has been discovered, which appears to have importance in the regulation of the activity of this ubiquitous family of enzymes and ultimately in the design of safer and more specifically acting drugs and environmental agents.
