New developments in the regulation of heme metabolism and their implications.

Various endogenous and exogenous chemicals, such as hormones, drugs, and carcinogens and other environmental pollutants are enzymatically converted to polar metabolites as a result of their oxidative metabolism by the mixed-function oxidase system. This enzyme complex constitutes the major detoxifying system of man and utilizes the hemoprotein--cytochrome P-450--as the terminal oxidase. Recent studies with trace metals have revealed the potent ability of these elements to alter the synthesis and to enhance the degradation of heme moiety of cytochrome P-450. An important consequence of these metal actions is to greatly impair the ability of cells to oxidatively metabolize chemicals because of the heme dependence of this metabolic process. In this report the effects of exposure to trace metals on drug oxidations is reviewed within the framework of metal alterations of heme metabolism, including both its synthesis and degradation, since these newly discovered properties of metals have made it possible to define a major dimension of metal toxicity in terms of a unified cellular mechanism of action.