Molecular Pharmacology, Vol 14, 900-910, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Alterations in Hepatic Heme Biosynthetic Capability and Mixed Function Oxidase Activity During Ethionine Exposure in Rats

¹ National Institutes of Health, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

These studies investigated the relationship between hepatic heme biosynthetic capability and mixed function oxidase activity in ethionine-treated rats. Animals fed a diet containing 0.25% D,L-ethionine for 2 to 3 months experienced up to a 65% decrease in hepatic aminopyrine demethylase activity and cytochrome P-450 and microsomal heme levels. These events were preceded by a loss of feedback repression of hepatic -aminolevulinic acid synthetase by heme and a 50% reduction in ferrochelatase activity as compared with that of untreated controls. A correlation between hepatic heme biosynthetic capability and mixed function oxidase activity was demonstrated in ethionine-fed animals using drugs and other agents which selectively alter heme biosynthetic pathway enzymes. These results indicate that specific changes in the regulation of hepatic heme biosynthesis occur during the early stages of ethionine exposure leading to decreased synthesis of microsomal heme and a relative deficiency of mixed function oxidase activities. It is suggested that heme may become rate-limiting with respect to microsomal mixed function oxidase activity under circumstances wherein heme biosynthesis has been chronically compromised.