In the past, we have identified heme oxygenase as distinct enzyme protein and defined the ability of toxic metal complexes and environmental chemicals to induce the activity of the enzyme. Heme oxygenase is rate-limiting in heme degradation pathway. In subsequent studies, we have shown that induction of heme oxygenase leads to perturbations in hemoprotein-dependent biotransformations such as drug, xenobiotic, and steroid metabolism; the organs affected include the brain , testis, ovary, adrenals and kidney, as well as the liver. Also, increase in activity of the enzymes was found related to the etiology of hyperbilirubinemia under hemolytic conditions. Recently, we have identified in rat organs the presence of two forms of the enzyme, HO-1 and HO-2. Although we have established that the two forms are distinct enzyme proteins and only HO-1 appears inducible, much remains to be learned about the enzymatic properties of the two forms. In addition to their effect on heme oxygenase, metal complexes were found to cause alterations in heme biosynthesis and GSH metabolism. GSH functions in detoxification processes by forming conjugates with xenobiotics, a reaction facilitated by GSH-S transferases. Transferases also function as transfer/binding proteins for numerous chemicals, including bilirubin and steroids. The overall objective of the proposed research is to further characterize the toxicological action of metal complexes at cell and molecular level by continuing the following ongoing research: 1) Characterization of the mechanism of heme degradation process. Specifically, efforts will be made to delineate the mechanism of interaction of HO-1 and HO-2, with NADPH-cyt P- 450 reductase, with respect to ligand binding sites and establish whether differences exist between interactions of the isozymes and the reductase. 2) Examination of the mechanism of inhibition of heme degradation and bilirubin formation by synthetic metalloporphyrins, and the biochemical and developmental consequences of their action. 3) Investigation of the effect of Mn-mediated alterations in brain hemoprotein metabolism on neurotransmitter metabolism. The dopaminergic function will be the focus of the study. 4) Delineation of the mechanism by which cis-platinum controls cytochrome P-450 and steroidogenesis in male reproductive system. Emphasis will be on hypothalamo- pituitary-gonadal axis. And, 5) examination of the pattern of alteration in the concentration of GSH-S-transferases in the kidney in response to cis-platinum.
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