Regulation of Rates of Ethanol Metabolism and Liver [NAD+]/[NADH] Ratio

Abstract

Factors that control the rate of alcohol metabolism in mammals have been the subject of debate for many years (for detailed reviews, see Crow, 1985; Crow and Hardman, 1989). There have been two main theories as to the major rate limitation on the ethanol metabolic pathway. The first theory was that the rate at which NADH (generated in the alcohol and aldehyde dehydrogenase reactions) could be reoxidised to NAD+ was limiting (Hawkins and Kalant, 1972; Khanna and Israel, 1980; Thurman et al, 1989). This theory arose from the observation that the ratio of free [NAD+]/[NADH] in liver cytosol decreased during ethanol metabolism. It was assumed either that the liver ran out of NAD+, because the rate of reoxidation of NADH was limiting, and this lack of NAD+ then limited the rate of the alcohol dehydrogenase (ADH) reaction (Khanna and Israel, 1980) or that NADH accumulated and caused product inhibition of ADH (Thurman et al, 1989). The second theory was that the amount of ADH present in the liver was the main rate-determining factor for the pathway (Crow et al, 1977; Cornell et al, 1979; Braggins and Crow, 1981; Cornell, 1983; Bosron et al, 1983). This theory arose in part from observations that the activity of liver ADH measured in vitro was only slightly more than necessary to explain rates of ethanol metabolism observed in vivo (Crow et al, 1977; Cornell et al, 1979; Braggins and Crow, 1981). ADH was not present ‘in excess’ as had sometimes been claimed (Hawkins and Kalant, 1972; Kalant et al, 1975). It was also observed that variations in ADH activity induced by castration (Rachamin et al, 1980; Mezey et al, 1980; Cicero et al, 1980, 1982), starvation (Braggins and Crow, 1981; Lumeng et al, 1979, 1980) or stress (Mezey et al, 1979) were associated with corresponding changes in rates of ethanol metabolism.