In recent years a number of toxicologically important heavy metal ions and transition elements have been recognized for their remarkable capacity to induce the activity of heme oxygenase, the rate-limiting enzyme in heme degradation. These effects are accompanied by perturbations in cellular heme, hemoprotein metabolism, and hemoprotein-dependent monooxygenase activities. Furthermore, it has been shown that the administration of toxic metal ions and the metalloid element, selenium, to animals results in marked alterations in cellular glutathione levels. Glutathione plays a central role in the detoxification of electrophilic metabolites of xenobiotics and reactive oxygen intermediates that can initiate chain reactions leading to cell injury. Glutathione also functions in detoxification processes by forming conjugates with xenobiotics, and reaction which is facilitated by GSH-S-transferases. The objectives of the proposed research are designed to expand our knowledge and understanding of metal ion toxicity and biological functions. Specific points to be investigated include: 1) the further characterization of the enzymes of heme degradation pathway, heme oxygenase and biliverdin reductase; 2) the continuation of our examination of the effect of toxic metal ions and metalloporphyrins on heme degradation activity in the newborn primates; 3) the exploration of the influence of toxic metal complexes on heme metabolism and the microsomal and mitochondrial hemoprotein turnover in the brain; 4) the further examination of the molecular basis for metal ion-mediated depletion of hepatic cytochrome P-450 concentration; 5) the investigation of the effect of toxic metal ions on heme metabolism and cytochrome concentration in the Leydig cells of testes, and adrenal cortex; 6) the further study of the regulation of biosynthesis of glutathione by selenium and toxic metal ions; and 7) the elucidation of the mechanism of increase in activities of glutathione-S-transferases by selenium and toxic metal ions.
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