Enhancement of hypoxic liver damage by ethanol. Involvement of xanthine oxidase and the role of glycolysis.
Using isolated hemoglobin-free perfused rat livers we investigated the hepatotoxic effects of hypoxia, ethanol or the combination of both. Hypoxia only (90 min) led to a weak toxicity as evidenced by the efflux of the enzymes glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH). This toxic effect was slightly higher in livers treated with ethanol (3 g/l) under normoxic conditions. Ethanol added under hypoxic conditions, however, showed a strong hepatotoxic effect. Under hypoxic conditions, lactate + pyruvate production was increased fivefold over control, indicating that glycolysis was more effectively undergone as main source of energy. Addition of ethanol suppressed this effect, indicating that ethanol inhibited glycolysis. These results indicate that ethanol potentiates hypoxic liver damage by inhibiting the main metabolic pathway yielding ATP under low oxygen tension resulting in a severe energy deficit. Allopurinol (100 mg/l) inhibited the toxic effects seen with ethanol + hypoxia. Also, the inhibitory action of ethanol on glycolysis was antagonized. Our results are consistent with the following model: hypoxia converts NAD-dependent xanthine dehydrogenase (XD) into the oxygen-dependent xanthine oxidase (XO). Due to hypoxia and ethanol, purine metabolites and acetaldehyde accumulate and are metabolized via XO. This process leads to the production of oxygen radicals which most probably mediate both the inhibition of glycolysis and the direct toxic effects towards liver cells.
D000079:Acetaldehyde / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D006019:Glycolysis / Q000187:drug effects; D000860:Hypoxia / Q000150:complications*; D007064:L-Iditol 2-Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D008297:Male; D011687:Purines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011687:Purines; D000431:Ethanol; D000493:Allopurinol; D000255:Adenosine Triphosphate; D007064:L-Iditol 2-Dehydrogenase; D014969:Xanthine Oxidase; D000410:Alanine Transaminase; D000079:Acetaldehyde