Drugs, environmental pollutants, as well as endogenous chemicals are thought to cause toxicity in many cases by covalently altering cellular components such as proteins. Over the last few years, we found that many agents are metabolized by hemoproteins, such as myoglobin, hemoglobin, or cytochromes P-450, into toxic reactive metabolites. In certain cases, these metabolites have been shown by us to cause the cross-linking of the heme prosthetic group to their respective protein moieties. This can lead not only to an inactivation of the hemoprotein, but also possibly to an activation of the hemoprotein. For example, last year we found that the cross-linking of heme of myoglobin to the polypeptide changed this protein from an oxygen-carrier into an oxidase that produces potentially toxic oxygen metabolites. This year we determined how myoglobin was likely converted into an oxidase, with the use of molecular modeling and computer graphics. It is also possible that synthetic hemoglobins, which are being developed as blood substitutes, might be modified in a similar manner, because we found that the heme prosthetic group of some of these drugs were modified, when the compounds were exposed to an oxidizing agent found in the body. This may explain, at least in part, some of the toxicities associated with these blood substitutes, such as vasospasm and reperfusion injury. In addition, we have shown that nitric oxide, an endogenously formed reactive intermediate with a multitude of biological effects, can inhibit cytochromes P-450, an important family of hemoproteins that metabolize xenobiotics and endogenous compounds. Thus, the bioregulatory function ascribed to nitric oxide may involve reactions with the prosthetic heme group of hemoproteins, in addition to that of cytosolic guanylyl cyclase.
