Metabolic controls in precancerous liver—VI. Studies in vivo and in vitro on feedback regulation of Δ-aminolevulinic acid synthetase in ethionine-fed rats

Abstract

We have studied induction of δ-aminolevulinic acid (ALA) synthetase by the drug allylisopropylacetamide and the ability of exogenous heme to repress such induction in normal rat liver, in the livers of rats fed the hepatocarcinogen, ethionine and in host livers and hepatomas of rats bearing Morris hepatomas 5123C, 7794A and 9618A. We also measured changes in tyrosine aminotransferase. In experiments in vivo, ALA synthetase was shown to be inducible in normal liver, in ethionine-treated liver, in host livers of hepatoma-bearing rats and in hepatoma 5123C. Under our conditions it was non-inducible in hepatomas 9618A and 7794A. In normal and host livers injected heme repressed drug-stimulated induction, but in ethionine-treated livers and in hepatoma 5123C this feedback-type repression by heme was absent. This apparent defect in metabolic control in both cancerous and precancerous liver parallels the similar loss of feedback control of cholesterol synthesis previously reported. In contrast to findings in vivo for ethionine-fed rats, heme repression was found to be fully operative when studied in vitro, i.e. in liver cells isolated from ethionine-treated rats. The possible significance of this difference between findings in vivo and in vitro, in relation to the nature of ethionine-induced changes in precancerous liver, is discussed.