The effect of chronic ethanol consumption on pathways of ethanol metabolism

The contribution of the known hepatic pathways for the disposal of ethanol was studied utilizing two different experimental designs. In vitro studies were carried out in hepatocytes isolated from rats fed Purina chow. Rates of ethanol oxidation in these preparations increased with increasing levels of ethanol (10-50 mM). After inhibition of alcohol dehydrogenase (ADH) by pyrazole (2 mM) and the catalase by azide (1 mM) approximately 25% of the ethanol oxidizing activity remained. The residual activity was also dependent upon ethanol concentration and the apparent Km was 13 mM. Hepatocytes from ethanol-fed rats exhibited rates of ethanol oxidation which were also dependent upon the concentration of ethanol. The rates were higher in the hepatocytes from the ethanol-fed rats than in the controls. The addition of inhibitors of ADH and catalase lowered the rates, but abolished neither the differences nor the concentration dependency. In the in vivo studies, ethanol elimination rates were measured in alcohol-fed and control baboons by using a constant ethanol infusion to maintain blood ethanol at three different levels: 5, 10 or 50 mM. Ethanol elimination rate was accelerated with increasing concentration, particularly in alcohol-fed baboons. These observations indicate that a pathway other than the low Km alcohol dehydrogenase participates in alcohol oxidation and is responsible in part for the adaptive increase in ethanol metabolism associated with chronic ethanol consumption.