Alterations Induced in Heme Pathway Enzymes and Monooxygenases by Gold

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 δ-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 δ-aminolevulinic acid dehydratase and ethylmorphine N-demethylase activities. Gold sodium thiomalate, administered acutely, altered heme biosynthetic pathway enzymes in erythrocytes, liver, and kidney. Erythrocyte δ-aminolevulinic acid dehydratase activity was decreased with a concomitant increase in protoporphyrin content. In the liver δ-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 δ-aminolevulinic acid synthase, δ-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, δ-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.