Enzymatic basis of metal ion alterations of cellular heme and glutathione metabolism.

It is becoming increasingly apparent that the enzymes of heme and GSH metabolism pathways are extremely sensitive to metal ions. It follows that alterations in the activities of the enzymes of heme metabolism are often reflected in the heme dependent cellular functions, particularly those which depend on cytochrome P-450. Moreover, perturbations in cellular GSH levels may alter the biological inactivation of the intermediates of cytochrome P-450 activity normally inactivated by GSH-conjugation. The effects of transition and heavy metal ions on the heme metabolism pathway are perhaps of particular significance when exerted on the two key enzymes of the pathway: the delta-aminolevulinate synthetase, the initial and the rate-limiting enzyme of the heme biosynthetic pathway, and heme oxygenase, the rate-limiting enzyme of heme degradation pathway. The activities of other enzymes of the heme metabolism pathway are also effected by metal ions; the nature of the effect is generally that of inhibition. Similarly, the inhibition by heavy metal ions of the activities of GSSG-reductase, gamma-glutamylcysteine synthetase, and gamma-glutamyl transpeptidase, which are the key enzymes of GSH metabolism, have toxicological significance. However, it is important to recognize that the presently discussed effects of metal ions do not necessarily have negative biological implications. The rather intricate and interrelated effects of metal ions on heme and GSH metabolism pathway under certain circumstances may have positive ramifications.