Is hypoxia involved in the mechanism of alcohol-induced liver injury?

Ronald G. Thurman, Sungchul Ji, Takakatsu Matsumura, John J. Lemasters

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Is Hypoxia Involved in the Mechanism of Alcohol-Induced Liver Injury? THURMAN, R. G., JI, S., MATSUMURA, T. LEMASTERS, J. J. (1984). Fundam. Appl. Toxicol. 4, 125-133. Since alcoholism is a major health problem, mechanisms responsible for various forms of alcoholic liver disease (e.g., fatty liver, alcoholic hepatitis, and cirrhosis) require elucidation. Knowledge of these mechanisms is needed to provide a sound framework to treat alcoholic liver disease, to prevent its occurrence and to identify those most susceptible to it. Israel and co-workers proposed that etnanol-induced necrosis results from hypoxia to centrilobular hepatocytes as a consequence of an alcohol-induced increase in hepatic oxygen utilization (Y. Israel, H. Kalant, H. Orrego, J. M. Khanna, L. Videla, and J. M. Phillips, 1975, Proc. Natl. Acad. Sci. USA, 72(3), 1137-1141). We have employed several new techniques to evaluate this hypothesis. Procedures have been developed to make measurements of hepatic metabolism within the hepatic lobule in the isolated, perfused liver using miniature light guides and oxygen electrodes. By comparing these lobular measurements to global metabolism and to hepatic morphology determined by light and electron microscopy, a coherent, quantitative description of lobular oxygen metabolism is emerging. With these techniques, the lobular oxygen gradient was measured directly in isolated, perfused rat livers. This gradient was elevated in livers from ethanol-treated rats, an effect which was blocked by the antithyroid drug, propylthiouracil. Restriction of oxygen delivery to the isolated liver produced stable, circumscribed zones of virtual anoxia localized around the central vein. Anoxic stress led within minutes to centrilobular injury with complete sparing of periportal areas. Cellular injury was characterized by the formation of membranous blebs on the surface of centrilobular hepatocytes. When hypoxic tissue was reoxygenated, blebs were released into the circulation. This cytoplasmic shedding may be responsible for the appearance of hepatic enzymes in the blood in liver disease. Our studies show clearly that ethanol can accentuate the oxygen gradient. Further, relatively brief periods of hypoxia can produce significant cellular injury. Therefore, data are consistent with the hypothesis that hypoxia is involved in the mechanism of ethanol-induced liver damage. However, data demonstrating that ethanol can produce centrilobular hypoxia in man and experimental animals, a key to this hypothesis, are still lacking.

Original languageEnglish (US)
Pages (from-to)125-133
Number of pages9
JournalToxicological Sciences
Issue number2 PART1
StatePublished - Apr 1984
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Toxicology

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