The Effect of Chronic Ethanol Consumption on Pathways of Ethanol Metabolism

Abstract

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 K_m 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 K_m alcohol dehydrogenase participates in alcohol oxidation and is responsible in part for the adaptive increase in ethanol metabolism associated with chronic ethanol consumption.

In the liver there are three different metabolic systems capable of oxidizing ethanol (Lieber, 1977). The contribution of each of these pathways to the disposal of ethanol under a variety of conditions has not been clarified. Traditionally, it has been assumed that the rate of ethanol elimination in vivo follows zero-order kinetics (i.e., is independent of blood ethanol concentrations) above the level of 5 mM (Plapp, 1975). This would imply that only the classic ADH pathway with its low K_m participates in the oxidation of ethanol. Recently this concept has been challenged. It has been demonstrated that ethanol elimination is faster at high than at low blood ethanol levels (Feinman et al., 1978) and that chronic ethanol consumption is associated with an increase in ethanol metabolism in man (Salaspuro and Lieber, 1978) and animals (Lieber and DeCarli, 1972). This increase in the rate of ethanol oxidation cannot be understood if one assumes involvement of the ADH pathway only. In an attempt to clarify this question, we utilized two different approaches. In the first study, we measured the rate of oxidation of ethanol (10–50 mM) in isolated liver cells obtained from chow and ethanol-fed rats in the presence and absence of pyrazole and azide, inhibitors of ADH and catalase respectively. In the second study we measured the rate of ethanol elimination in our baboon model at three different blood levels of ethanol.