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.
Highlights
The pharmacologic and potentially pathologic effects of alcohol depend on the concentrations of ethanol and its metabolites in the body, and on the duration of exposure to these substances
In order to clarify the roles of ADH1 and ADH3 in systemic alcohol metabolism and in the action of alcohol in the body at various ethanol doses, we investigated the rate of alcohol metabolism (EDR: mg/kg/h) in wild-type mice (Wild), ADH1-null mutant mice (Adh1-/-) and ADH3-null mutant mice (Adh3-/-) by the administration of ethanol at doses ranging from 1.0 to 4.5 g/kg [25]
This review described a new view of Alcohol dehydrogenase (ADH) 3 in the fields of alcohol metabolism and the bioaction of ethanol, and compared the new face of ADH3 to the well-known ADH1
Summary
The pharmacologic and potentially pathologic effects of alcohol depend on the concentrations of ethanol and its metabolites in the body, and on the duration of exposure to these substances. Mammalian livers are known to contain two ADH isozymes other than ADH1, namely, ADH2 (Class II) and ADH3 (Class III), both of which have a higher Km for ethanol than ADH1 [32] These data suggest a possible role for these high-Km ADHs in the non-ADH1 pathway of alcohol metabolism. Compared to the EDR of Wild, that of Adh3-/- decreased markedly as ethanol dose increased and was about 66% of that of Wild at a dose of 4.5 g/kg These data demonstrate that ADH3 contributes to systemic alcohol metabolism in a dose-dependent manner in vivo, with the contribution being over 30% at large doses. The frequency of mortality at large doses increased in the order Adh1-/-, Adh3-/-, and Wild These data demonstrate that, in vivo, ADH3 diminishes acute alcohol intoxication together with ADH1, by participating in alcohol metabolism in a dose-dependent manner
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