Pathways of ethanol metabolism in perfused rat liver

Abstract

The primary pathway of hepatic ethanol metabolism involves alcohol dehydrogenase. Hydrogen generated from ethanol metabolism enters the mitochondrial space most likely as malate over a substrate shuttle mechanism, and is subsequently oxidized by the mitochondrial respiratory chain. The rate-limiting step in this overall multicompartmental process is the rate of reduced cofactor (NADH) reoxidation by the respiratory chain. Since the electron flux in the respiratory chain is controlled by the ADP supply, alcohol dehydrogenase-dependent ethanol metabolism can be activated by perturbations which circumvent the rate-limiting step, such as artificial electron acceptors, gluconeogenic precursors, and uncoupling agents. Moreover, an ATP utilizing process is responsible for the stimulation of ethanol metabilism observed following chronic pretreatment with ethanol. In perfused rat liver catalase also participates in ethanol metabolism to a lesser extent than alcohol dehydrogenase. Quantitative assessments indicate that the predominant ethanol oxidase at low ethanol concentrations (less than 20 mM) is a alcohol dehydrogenase; however, at higher ethanol concentrations, a significant portion of total ethanol metabolism (up to 50%) is mediated by catalase-hydrogen peroxide complex. This pathway is limited by the rate of generation of hydrogen peroxide in the hepatocyte, and can be stimulated with substrates for intraperoxisomal hydrogen peroxide generation such as glycolate, urate and D-amino acids. Considerable evidence implicates catalase-hydrogen peroxide complex in the mechanism of NADPH-dependent microsomal ethanol oxidation.