Toxic Effects of Metals on the Synthesis and Disposition of Heme

Abstract

The heme biosynthetic pathway is perturbed by many chemicals and metals, and heme and hemoprotein biosynthesis may be disrupted as a result of exposure to these agents. Cobalt treatment of rats leads to marked decreases in the rate of heme biosynthesis and in the level of hemoproteins in hepatic microsomes. Cardiac heme biosynthesis in isolated perfused rat hearts is also decreased as a result of cobalt-induced decreases of δ-aminolevulinic acid synthetase activity. Lead acetate does not inhibit either heme biosynthesis or δ-aminolevulinic acid synthetase activity in isolated perfused rat hearts. Fasting of rats, which may lead to increases in hepatic δ-aminolevulinic acid synthetase activity, leads to a rapid and extensive decrease in cardiac δ-aminolevulinic acid synthetase activity and a marked decrease in the rate of cardiac heme biosynthesis. Friend erythroleukemic cells which can be induced by dimethylsulfoxide to synthesize hemoglobin show an increase in δ-aminolevulinic acid synthetase activity in response to cobalt exposure, and mutant forms of these cells which cannot be induced to synthesize hemoglobin because of a deficiency in ferrochelatase activity display an increase in δ-aminolevulinic acid synthetase activity when exposed to cobalt. Therefore, cobalt treatment may lead to different effects on the heme biosynthetic pathway in different tissues. This response may be dependent on the physiologic function of the organ and the degree of control imposed by the end product, heme, on the rate-limiting step of the pathway, δ-aminolevulinic acid synthetase.