Metabolic pharmacokinetics of early chronic alcohol consumption mediated by liver alcohol dehydrogenases 1 and 3 in mice

Background and aim: Alcohol dehydrogenases (ADHs) 1 and 3 are responsible for systemic alcohol metabolism. The current study investigated the contribution of liver ADH1 and ADH3 to the metabolic pharmacokinetics of chronic alcohol consumption (CAC).

Methods: The 9-week-old male mice of different ADH genotypes (wild-type [WT], Adh1^-/- , and Adh3^-/- ) were administered with 10% ethanol solution for 1 month, followed by acute ethanol administration (4.0 g/kg). The alcohol elimination rate (AER), area under the blood alcohol concentration curve (AUC), and the maximum blood alcohol concentration (C_max ) were calculated. The liver content, activity, and mRNA levels of ADH were evaluated.

Results: Chronic alcohol consumption increased the AER and reduced the AUC in all ADH genotypes. The increased ADH1 content was correlated with AER in WT mice but not in the Adh3^-/- mice. Similarly, the increased ADH3 content was also correlated with AER in both WT and Adh1^-/- mice. The C_max was significantly higher in Adh3^-/- control mice than in WT control mice. It decreased in the Adh1^-/- mice by CAC along with an increase in the ADH3 content.

Conclusions: Alcohol dehydrogenases 1 and 3 would accomplish the pharmacokinetic adaptation to CAC in the early period. ADH1 contributes to the metabolic pharmacokinetics of CAC with a decrease in AUC in conjunction with an increase of AER by increasing the enzyme content in the presence of ADH3. ADH3 also contributes to a decrease in AUC in conjunction with not only an increase in AER but also a decrease in C_max by increasing the enzyme content.