Gold salts are heavy metal compounds which are of biochemical and toxicological interest because they are presently being used in the treatment of rheumatoid arthritis. Twenty to 30% of patients treated with gold show disease remission. Organometals are of particular interest in relation to cytochrome P-450 and the enzymes of heme synthesis and degradation because they contain in addition to bound organic substituents, a central metal atom. Many metal ions produce significant losses of cytochrome P-450 and have a potent ability to alter by induction, repression, or other mechanisms key enzymes of heme degradation and synthesis. The proposed studies relate specifically to the effects of two gold salts currently in clinical use, namely gold sodium thiomalate and the recently introduced oral gold compounds, triethylphosphine gold. The heme biosynthetic pathway contains two sulfhydryl containing enzymes, Delta-aminolevulinic acid dehydratase and ferrochelatase, which are particularly sensitive to inhibition by heavy metals. Heme serves as a prosthetic group for cytochromes P-450, as well as other cytochromes, such as mitochondrial cytochromes. The cytochrome P-450-dependent enyzmes play a central role in the detoxification and/or activation of a large number of drugs and environmental pollutants to which the body may be exposed. Heme itself is degraded by the enzyme, heme oxygenase to bilirubin. Alterations in heme degradation, such as the induction of heme oxygenase by certain heavy metals, are generally accompanied by alterations in heme biosynthesis and in cytochrome P-450-dependent drug oxidations. Arthritic patients receiving gold therapy may also ingest other drugs. A toxic manifestation of exposure to gold salts will result in alterations in the rates of metabolism and hence the pharmacologicl action of these other drugs. In the proposed studies, the interaction of the two clinically used gold compounds, with inducers and inhibitors of drug metabolism and with other xenobiotics will be examined. It is the underlying assumption in the proposed studies that alterations in heme metabolism elicited by gold therapy will affect the functional capacity of the hemeprotein cytochrome P-450, and hence alter the pharmacological and toxicological action of drugs and other foreign compounds to which arthritic patients may be exposed.
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