Oxidant injury to hepatic mitochondrial lipids in rats with dietary copper overload. Modification by vitamin E deficiency.
To examine the role of oxidant damage to subcellular membranes in the pathogenesis of copper hepatotoxicity, the effects of dietary copper overload and varying states of vitamin E on biochemical, histological, and ultrastructural features of rat liver were investigated. Weanling male rats were pair-fed for 8 weeks on diets containing normal or high levels of copper in combination with either deficient, sufficient, or excessive vitamin E. Hepatic microsomes and mitochondria, isolated by differential centrifugation, showed similar enrichment and recovery among all experimental groups. Evidence of in vivo peroxidation of membrane lipids (generation of conjugated dienes and thiobarbituric acid reacting substances) was present in mitochondrial but not microsomal preparations from copper-overloaded rats. Serum aspartate aminotransferase, alanine aminotransferase, and cholylglycine (which were increased in all copper-overloaded rats), as well as mitochondrial thiobarbituric acid-reacting substances, were more elevated in vitamin E-deficient rats. In copper-overloaded rats, liver histology showed changes of acute and chronic hepatocyte injury with mild periportal fibrosis; electron microscopy showed abundant copper-containing lysosomes and dilated cristae of hepatocyte mitochondria, findings similar to those in the liver of humans with copper-overload disorders. These findings suggest that an oxidant injury to hepatocyte mitochondria may be one of the initiating factors in hepatocellular damage that leads to hepatic lesions in copper-overload states in humans.
Department of Pediatrics, Children's Hospital, Denver, Colorado.
R J
RJ
Sokol
M
M
Devereaux
G W
GW
Mierau
K M
KM
Hambidge
R H
RH
Shikes
D000818:Animals; D003300:Copper / Q000008:administration & dosage / Q000633:toxicity*; D015227:Lipid Peroxidation; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism*; D008854:Microscopy, Electron; D008862:Microsomes, Liver / Q000378:metabolism / Q000648:ultrastructure*; D008930:Mitochondria, Liver / Q000378:metabolism / Q000648:ultrastructure*; D051381:Rats; D011919:Rats, Inbred Strains; D014810:Vitamin E / Q000502:physiology; D014811:Vitamin E Deficiency / Q000378:metabolism*
D008563:Membrane Lipids; D014810:Vitamin E; D003300:Copper