Alteration of hepatic microsomal structure and function by indium chloride. Ultrastructural, morphometric, and biochemical studies

Abstract

The effects of indium-chloride (InCl3) on hepatocyte structure and function were studied in male rats injected with doses of 0, 10, 20, or 40 mg of InCl3/kg and killed after 16 hours. Fragmentation and degranulation of the rough endoplasmic reticulum and increased numbers of In- and Fe-containing autophagic lysosomes were the most marked cellular changes observed by electron microscopy. Morphometric analyses of hepatocytes disclosed a maximal 4-fold increase in the volume density of the lysosome compartment and a 2-fold decrease in the volume density of the vacuole compartment. Surface densities of the mitochondrial cristae and rough endoplasmic reticulum were increased by 1.5-fold, whereas the surface densities of the smooth endoplasmic reticulum showed a maximal increase of 7-fold. These structural changes were associated with inhibition of microsomal aniline hydroxylase by as much as 50% and ethoxyresorufin-O-deethylase by as much as 30% but no change in aminopyrine demethylase activity. Microsomal acid phosphatase activity was also decreased to 74% of control, whereas beta-glucuronidase was unchanged. Mild inhibition of mitochondrial respiratory function but no changes in marker enzyme activities were noted. Lysosomal marker enzyme activities were also unaffected, with the exception of acid phosphatase, which was maximally decreased to 55% of control. The data indicate that acute InCl3 injection produces a primary effect on hepatocyte endoplasmic reticulum structure with attendant changes in both heme- and nonheme-dependent biochemical functions. These findings suggest that altered regulation of hepatic microsomal heme metabolism by indium and other metals occurs as part of a general process involving degradative changes in the endoplasmic reticulum structure due to membrane damage with subsequent lysosomal autophagy of nonfunctional components.