A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3)

Abstract

The conventional view is that alcohol metabolism is carried out by ADH1 (Class I) in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III), which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km) is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg). These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (β, CLT, AUC) of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases, as alcohol intake increases. Furthermore, ADH3 is induced in damaged cells that have greater hydrophobicity, whereas ADH1 activity is lower when there is severe liver disease. These data suggest that chronic binge drinking and the resulting liver disease shifts the key enzyme in alcohol metabolism from low-Km ADH1 to high-Km ADH3, thereby reducing the rate of alcohol metabolism. The interdependent increase in the ADH3/ADH1 activity ratio and AUC may be a factor in the development of alcoholic liver disease. However, the adaptive increase in ADH3 sustains alcohol metabolism, even in patients with alcoholic liver cirrhosis, which makes it possible for them to drink themselves to death. Thus, the regulation of ADH3 activity may be important in preventing alcoholism development.

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

“…In particular, ADH3 (the isoform belonging to class III according to the old nomenclature may participate to ethanol metabolism together with ADH1 or compensating for its reduced contribution (Haseba et al, 2003). In addition, it was suggested that chronic binge drinking might shift the key metabolic pathway from ADH1 to ADH3 (Haseba and Ohno, 2010), therefore attributing ADH3 a more critical role at high ethanol concentrations. Notably, 4-MP inhibits ADH1 but not ADH3 (Haseba and Ohno, 1997).…”

Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

“…Following parenteral administration of ethanol, these mice displayed an increased sleep time and embryonic resorption was increased 3-fold [9]. While ADH1 is thought to be responsible for the majority of ethanol metabolism in the liver, new pharmacokinetic evidence suggests a role for other ADH isoforms as well [48]. Therefore, this model may be useful in determining the pathophysiological importance of compensatory ADH isoforms as well as elucidating the kinetics of these enzymes for ethanol.…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…A plausible explanation is that chronic exposure to ethanol leads to hyperinsulinemia [125], which shifts energy supply from glucose to ketone bodies [65]. In turn, high ketone bodies alongside oxidized carbohydrates and iron overload shift ethanol metabolism from low Km ADH1 (that works in the millimolar range) to high Km alcohol-metabolizing enzymes (that work in the molar range) [65,141] such as cytochrome P450 2E1 (CYP2E1), ADH4, and ADH3 [28,30,66,69,126,142,143]. The net result is that large amounts of ethanol may cause organ damage concurrently with negligible BACs (Figure 2) [28,30,[65][66][67][68].…”