Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.
OBJECTIVE
Copper overload leads to liver injury in humans with Wilson's disease and in Bedlington terriers with copper toxicosis; however, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepatic mitochondria is involved in naturally occurring copper toxicosis.


METHODS
Fresh liver samples were obtained at the time of liver transplantation from 3 patients with Wilson's disease, 8 with cholestatic liver disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 copper-overloaded and 4 normal Bedlington terriers and from 8 control dogs. Hepatic mitochondria and microsomes (humans only) were isolated, and lipid peroxidation was measured by lipid-conjugated dienes and thiobarbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured.


RESULTS
Lipid peroxidation and copper content were significantly increased (P < 0.05) in mitochondria from patients with Wilson's disease and copper-overloaded Bedlington terriers. More modest increases in lipid peroxidation were present in microsomes from patients with Wilson's disease. Mitochondrial copper concentrations correlated strongly with the severity of mitochondrial lipid peroxidation. Hepatic alpha-tocopherol content was decreased significantly in Wilson's disease liver.


CONCLUSIONS
These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and that oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.
Section of Pediatric Gastroenterology and Nutrition, University of Colorado School of Medicine, Denver.
R J
RJ
Sokol
D
D
Twedt
J M
JM
McKim
M W
MW
Devereaux
F M
FM
Karrer
I
I
Kam
G
G
von Steigman
M R
MR
Narkewicz
B R
BR
Bacon
R S
RS
Britton
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003300:Copper / Q000009:adverse effects / Q000378:metabolism / Q000506:poisoning*; D004285:Dogs; D005260:Female; D006527:Hepatolenticular Degeneration / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology*; D016877:Oxidants / Q000009:adverse effects* / Q000378:metabolism; D012044:Regression Analysis; D014810:Vitamin E / Q000378:metabolism
D016877:Oxidants; D014810:Vitamin E; D003300:Copper