Molecular Pharmacology, Vol 14, 1176-1188, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Alterations Induced in Heme Pathway Enzymes and Monooxygenases by Gold

¹ Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20014, and Department of Pharmacology, Cornell University Medical College, New York, New York 10021

In this study, the effects of the gold compound, gold sodium thiomalate, on the heme biosynthetic pathway, on cytochrome P-450-dependent monooxygenases, and on heme catabolism were examined. The addition of the gold compound, in vitro, resulted in the inhibition of hepatic -aminolevulinic acid dehydratase, NADPH-cytochrome c reductase, and ethylmorphine N-demethylase activities. There was also a slight decrease in cytochrome P-450 content. Gold was a noncompetitive inhibitor of both -aminolevulinic acid dehydratase and ethylmorphine N-demethylase activities.

Gold sodium thiomalate, administered acutely, altered heme biosynthetic pathway enzymes in erythrocytes, liver, and kidney. Erythrocyte -aminolevulinic acid dehydratase activity was decreased with a concomitant increase in protoporphyrin content. In the liver -aminolevulinic acid dehydratase and ferrochelatase activities were significantly inhibited and the microsomal heme content was significantly decreased. In the kidney, the major site of gold deposition, the activities of -aminolevulinic acid synthase, -aminolevulinic acid dehydratase, and ferrochelatase were markedly inhibited and total porphyrin content was markedly decreased.

After acute gold treatment, monooxygenase activities in liver and kidney were decreased. Cytochrome P-450 content of both tissues decreased significantly and ethylmorphine N-demethylase and benzo(a)pyrene hydroxylase activities were both inhibited. NADPH-cytochrome c reductase activity, however, was not altered. In contrast to its inhibitory effects on the heme biosynthetic pathway and cytochrome P-450-dependent monooxygenases, gold caused a 1.5- and 8-fold induction in the liver and kidney, respectively, of microsomal heme oxygenase activity, the rate-limiting enzyme in the catabolism of heme.

There was no change in any of the parameters in the liver or erythrocytes after chronic treatment with gold. In the kidney, -aminolevulinic acid dehydratase activity and total porphyrins were significantly decreased. However, as in the liver, cytochrome P-450 content was not significantly altered. These results indicate that an adaptive response develops during chronic gold treatment which prevents the depression of heme biosynthesis and the formation of cytochrome P-450.

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ACKNOWLEDGMENTS The authors wish to thank Mrs. Nanci Brice for secretarial assistance.