The overall purpose of this proposal is to investigate the effects of various heavy metals ont the synthesis and degradation of both heme and various hemoproteins in the P450 superfamily. Heavy metals such as Cd, Ni, Cr, As and Pb induce heme oxygenase, the rate-limiting enzyme in the degradation of heme, and decrease levels of cytochrome P450. Previous studies have not distinguished the role of heme oxygenase versus metal- induced oxidative damage in the breakdown of heme and decrease in cytochrome P450. In addition, metals may affect the synthesis of P450. Pb and other metals also effect different steps of the heme biosynthetic pathway. Pb increases urinary secretion of 5-aminolevulinate (ALA) and coproporphyrin, and accumulation of zinc protoporphyrin in reticulocytes. Other heavy metals such as As and Cd have also been shown to affect excretion of coproporphyrin. Accumulation of zinc protoporphyrin in lead toxicity is attributed to incorporation of zinc by ferrochelatase due to deficiency of reduced iron, rather than to inhibition of ferrochelatase activity per se. It is not known how lead causes this deficiency of reduced iron or how metals mediate the accumulation of coproporphyrin. In this proposal, we will investigate: 1. The role of heme oxygenase induction versus oxidative damage in heavy metal-metal-mediated degradation of hepatic heme and cytochrome P450. We also will investigate the effect of heavy metals on the synthesis of P450. These studies will use primary cultures of rat hepatocytes. 2. The mechanisms underlying the effect of heavy metals to inhibit terminal steps of the heme biosynthetic pathway and increase accumulation of zinc protoporphyrin and excretion of urinary coproporphyrin. As part of these investigations, we expect to define the role of intracellular reductants to maintain reduction of Fe and prevent oxidation of coproporphyrinogen to coproporphyrin. These investigations will use primary cultures of rat and chick hepatocytes, rat kidney cells, rabbit erythroid cells and mitochondria isolated from rat liver and kidney.

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Dartmouth College
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