In this perspective we have described a newly characterized pathway for the metabolism of the prosthetic
heme of
cytochrome P-450, which results in the formation of
protein-bound adducts. This reaction occurs when the
cytochrome P-450 metabolizes a variety of
xenobiotics as well as endogenous compounds such as
hydrogen peroxide and
lipid hydroperoxides. It also takes place during the reactions catalyzed by other hemoproteins, such as
myoglobin and
hemoglobin. In the case of the reaction of ferrous
myoglobin with BrCCl3, under single-turnover conditions, an intact
heme moiety becomes covalently bound to an active-site
amino acid. This covalently altered
protein has significantly enhanced reductive activity compared to that of native
myoglobin, as demonstrated by its rapid reduction of molecular
oxygen and CCl4. It also is more rapidly proteolyzed than
myoglobin. These findings may have relevance to the P-450
cytochromes in which suicide inactivation, destruction of the
heme prosthetic group, and loss of the
protein is observed. The activation of hemoproteins to
heme-protein adducts may also have toxicological significance, perhaps in
oxygen reperfusion injury in the myocardium as well as other tissues by enhancing the production of
oxygen-derived radicals from molecular
oxygen and
lipid hydroperoxides. Clearly, further research in the characterization of
heme-protein adducts is necessary before their importance in
protein turnover and
oxygen-induced injury can be determined.