Involvement of cell oxidant status and redox state in the increased non-enzymatic ethanol oxidation by the regenerating rat liver

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Graphical abstractEthanol administration is capable of inhibiting or delaying the partial hepatectomy (PH)-induced liver regeneration, probably altering liver metabolism by means of its oxidative metabolism. Since the regenerating liver has increased capacity for oxidizing ethanol, the present study was aimed to address the contribution of the ethanol-oxidizing metabolic pathways in the regenerating liver cells. Isolated hepatocytes were prepared from control livers and from animals subjected to two-thirds PH. In both preparations, ethanol oxidation was largely increased by incubation with glucose and was highly sensitive to inhibitors of ethanol-oxidizing enzymatic pathways (alcohol dehydrogenase, catalase and cytochrome P-4502E1 activities). The latter led to a total blockade of ethanol disposal by control hepatocytes, while liver cells from PH-rats only showed an early 70–75% inhibition of ethanol catabolism with the inhibitors used. In regenerating hepatocytes, the enhanced ethanol oxidation was blocked by scavengers of reactive oxygen species, an effect that correlated with enhanced cytoplasmic lipid peroxidation by-products. Both cell preparations showed similar sensitivity to inhibitors for the malate-aspartate shuttle and mitochondrial electron transport chain; the shift of the cytoplasmic redox state was also quite similar after ethanol oxidation. A more oxidized mitochondrial redox state was found in hepatocytes from PH-rats and more shifted to the reduced state during ethanol oxidation this effect was not abolished by inhibiting alcohol dehydrogenase activity. In conclusion, data clearly show that an important fraction of ethanol is metabolized through a non-enzymatic-mediated oxidative event, which could largely contribute to the deleterious effect of ethanol on the proliferating liver.

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