Pyridine Nucleotides and Ethanol

Abstract

It is well established that ethanol is oxidized to acetate in the liver, and that reducing equivalents are formed in the process (1, 2). During these reactions there is a marked shift in the oxidation-reduction level of the liver to a more reduced state, suggesting that reducing equivalents are being formed at rates which exceed the hepatocytes’ capacity to handle them (3–11). Concomitant with this alteration in redox state there is a lack of any significant change in the oxygen consumption of the liver, an inability of the liver to store ethanol, and an apparent lack of any feed-back control mechanism for the regulation of ethanol oxidation (10–13). This suggests that ethanol is used as a preferred substrate, and the reducing equivalents formed during its oxidation therefore compete with the hydrogen ions produced in other metabolic pathways. Although the rate-limiting step in the oxidation of ethanol has not been precisely defined, it appears that, in vivo, the activities of the enzymes involved are not rate-limiting, but rather that the reactions are limited by the re-oxidation of NADH (14–16). Under these circumstances it is the cell’s capacity to handle these reducing equivalents that regulates the rate of removal of ethanol, and determines the change in flux of substrates in other metabolic pathways. Recent data obtained in my laboratory agree with much of the literature and indicate that the hepatocytes’ capacity to handle the excess reducing equivalents depends on the activity of systems involved in translocating these ions into the mitochondria and on the activity of the respiratory chain. These processes are affected not only by the dose but also by the mode of administration of ethanol (acute or chronic) as well as by the nutritional and hormonal status of the animal. These data will be reviewed here.