Chronic ethanol treatment induces H2O2 production selectively in pericentral regions of the liver lobule.
Chronic treatment with ethanol damages pericentral regions of the liver selectively, and reactive oxygen species such as H2O2 may be involved in the mechanism of hepatotoxicity. To test this idea, the effect of chronic treatment with ethanol on rates of H2O2 production was measured in tissue cylinders isolated from periportal and pericentral regions of livers from ethanol-treated rats. Rates of hydrogen peroxide production, assessed from the oxidation of methanol to formaldehyde by catalase-H2O2, were similar in tissue cylinders isolated from periportal regions in control and ethanol-treated rats. In contrast, rates of H2O2 production were over 4-fold higher in tissue isolated from pericentral regions of livers from ethanol-treated than control animals (1.7 +/- 0.5 vs. 0.4 +/- 0.3 nmol/min/mg protein, respectively). Rates of H2O2-generating acyl CoA oxidase activity were equivalent in tissue cylinders from periportal regions of livers from both groups (approximately 2 nmol/min/mg protein), but were over 2-fold higher in tissue cylinders from pericentral regions of livers from ethanol-treated rats than from controls. In contrast, catalase activity was increased nearly 2-fold in homogenates from both periportal and pericentral regions by ethanol treatment while glutathione peroxidase activity was decreased significantly in both regions. These data demonstrate that ethanol increases H2O2 generation in pericentral regions of the liver lobule in part by elevating rates of peroxisomal beta-oxidation of acyl CoA compounds and are consistent with the hypothesis that local increases in H2O2 production may be involved in the mechanism of ethanol-induced hepatotoxicity.
Misra
U K
UK
Department of Pharmacology, University of North Carolina, Chapel Hill 27599-7365.
Bradford
B U
BU
Handler
J A
JA
Thurman
R G
RG
D000214:Acyl Coenzyme A / Q000378:metabolism; D042962:Acyl-CoA Oxidase; D000437:Alcoholism / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D002374:Catalase / Q000378:metabolism; D000431:Ethanol / Q000493:pharmacokinetics; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000473:pathology*; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000214:Acyl Coenzyme A; D000431:Ethanol; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D002374:Catalase; D005979:Glutathione Peroxidase; D042962:Acyl-CoA Oxidase