The importance of cycling of blood alcohol levels in the pathogenesis of experimental alcoholic liver disease in rats

Background & Aims: Rats fed ethanol at a constant rate through a permanent intragastric cannula have a regular fluctuation in blood alcohol level (BAL) and urine alcohol level (UAL). The level of ethanol peaks every 6–10 days. The question is how the liver differs at the peaks and troughs of the UAL cycle. Hypoxic injury is postulated to occur at the peaks. Therefore, liver injury may be different at the peaks and troughs. Methods: Many parameters were measured at the peaks, troughs, and controls for comparison. Results: Indicators of hypoxic injury at the peaks included ATP reduction, a shift to the reduced state in the NADH/NAD ratio, an increase in expression of vascular endothelial growth factor, an increase in the pathology score at the peaks, and an increase in adduct formation using pimonidazole. Liver nitrites, number of granulocytes, liver weight/body weight ratio, cytochrome P450 2E1 protein, and chymotrypsin-like activity changed in the same direction compared with control values. Conclusions: The results indicate that hypoxic injury occurs at the peaks. There was a marked shift in NADH/NAD redox state at the peaks caused by hypoxia. This shift could account for the reduced rate of ethanol elimination by alcohol dehydrogenase at the peaks. GASTROENTEROLOGY 2002;123:325-335