OXIDANT INJURY TO HEPATIC MITOCHONDRIA IN PATIENTS WITH WILSONS-DISEASE AND BEDLINGTON TERRIERS WITH COPPER TOXICOSIS

Background/Aims: Copper overload leads to liver injury in humans with Wilson's disease and in Bedlington terriers with copper toxicosis; how ever, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepat ic mitochondria is involved in naturally occurring copper toxicosis. M ethods: Fresh liver samples were obtained at the time of liver transpl antation from 3 patients with Wilson's disease, 8 with cholestatic liv er disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 cop per-overloaded and 4 normal Bedlington terriers and from 8 control dog s. Hepatic mitochondria and microsomes (humans only) were isolated, an d lipid peroxidation was measured by lipid-conjugated dienes and thiob arbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured. Results: Lipid peroxidation and copper content w ere significantly increased (P < 0.05) in mitochondria from patients w ith Wilson's disease and copper-overloaded Bedlington terriers. More m odest increases in lipid peroxidation were present in microsomes from patients with Wilson's disease. Mitochondrial copper concentrations co rrelated strongly with the severity of mitochondrial lipid peroxidatio n. Hepatic alpha-tocopherol content was decreased significantly in Wil son's disease liver. Conclusions: These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and th at oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.