Abnormal hepatic mitochondrial respiration and cytochrome C oxidase activity in rats with long-term copper overload.
BACKGROUND
Dietary copper overload in the rat is associated with morphological abnormalities and lipid peroxidation of hepatic mitochondria. This study was designed to determine if copper hepatotoxicity was associated with functional alterations in mitochondrial respiration in conjunction with lipid peroxidation.


METHODS
Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with sufficient vitamin E. Serum and liver samples were obtained, and hepatic mitochondria were isolated by differential centrifugation.


RESULTS
Oxidant injury (decreased levels of hepatic glutathione and alpha tocopherol and increased levels of mitochondrial thiobarbituric acid-reacting substances) was present in the copper-overloaded rats. Serum aminotransferase levels correlated with concentrations of mitochondrial copper and thiobarbituric acid-reacting substances. Copper overload caused a decrease in state 3 respiration and the respiratory control ratio in hepatic mitochondria when several electron donors were used. Analysis of the oxidoreductase activities of the four mitochondrial electron transport protein complexes showed that complex IV (cytochrome C oxidase) activity was reduced by 60% in copper overload.


CONCLUSIONS
Functional abnormalities of mitochondria accompany lipid peroxidation and the morphological alterations caused by copper overload, supporting the hypothesis that the mitochondrion is one of the major intracellular targets in copper hepatotoxicity.
Section of Pediatric Gastroenterology and Nutrition, University of Coloarado School of Medicine, Denver.
R J
RJ
Sokol
M W
MW
Devereaux
K
K
O'Brien
R A
RA
Khandwala
J P
JP
Loehr
D000818:Animals; D003300:Copper / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003300:Copper; D003576:Electron Transport Complex IV; D005978:Glutathione