The role of lysosomes in the pathogenesis of copper-induced hepatotoxicity

Abstract

The effects of altered lysosomal function on the pathogenesis of copper-induced hepatotoxicity were studied in beige and conventional mice. Copper loading was accomplished through daily intraperitoneal injections of aqueous copper chloride (8 mg/kg) for 1, 2, and 4 weeks. Selected tissues for morphologic studies, determination of intracellular copper distributions, and measurements of lysosomal lipoperoxides were collected after 0, 7, 14, and 28 days of treatment. In an additional study, beige and conventional mice receiving intraperitoneal injections of copper for 10 days were treated subsequently with oral chloroquine (120 mg/kg), and lysosomal labilization was measured as percent unbound acid phosphatase. Hepatic lesions resulting from progressive copper loading developed more quickly and were more severe in beige mice than in conventional mice. The primary hepatocellular lesion was demonstrated by light and transmission electron microscopy to be accelerated autophagocytosis. Beige mice had consistently higher levels of copper in the nuclear (N) and cytosolic (Cy) fractions with lower levels in the heavy (HM) and light (LM) mitochondrial fractions than did conventional mice. Levels of total hepatic copper were similar in both groups of mice except at day 14, when beige mice had higher levels. ...