Metabolic pharmacokinetics of early chronic alcohol consumption mediated by liver alcohol dehydrogenases 1 and 3 in mice
Metabolic pharmacokinetics of early chronic alcohol consumption mediated by liver alcohol dehydrogenases 1 and 3 in mice
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DOI：
10.1111/jgh.14260
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发表时间：
2018-11-01
影响因子：
4.1
通讯作者：
Ohno, Youkichi
中科院分区：
文献类型：
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作者：
Okuda, Takahisa;Haseba, Takeshi;Ohno, Youkichi
背景和目的乙醇脱氢酶（ADHs） 1和3负责全身酒精代谢。本研究探讨肝脏ADH1和ADH3对慢性酒精消耗（CAC）代谢药代动力学的贡献。方法9周龄不同ADH基因型（野生型[WT]、Adh1（-/-）和Adh3(-/-)）的雄性小鼠，分别给予10%乙醇溶液1个月，然后急性给药（4.0g/kg）。计算酒精消除率（AER）、血液酒精浓度曲线下面积（AUC）和最大血液酒精浓度（C-max）。测定肝脏ADH的含量、活性和mRNA水平。结果慢性饮酒增加了所有ADH基因型的AER，降低了AUC。ADH1含量的增加在WT小鼠中与AER相关，而在Adh3（-/-）小鼠中与AER无关。同样，在WT和Adh1（-/-）小鼠中，ADH3含量的增加也与AER相关。Adh3（-/-）对照小鼠的C-max明显高于WT对照小鼠。在Adh1（-/-）小鼠中，CAC降低了Adh1(-/-)，增加了ADH3的含量。结论乙醇脱氢酶1和3在早期完成了对CAC的药动学适应。ADH1对CAC的代谢药代动力学有贡献，在ADH3存在的情况下，通过增加酶含量降低AUC，同时增加AER。ADH3不仅增加了AER，还通过增加酶含量降低了C-max，从而降低了AUC。
Background and AimAlcohol 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).MethodsThe 9-week-old male mice of different ADH genotypes (wild-type [WT], Adh1(-/-), and Adh3(-/-)) were administered with 10% ethanol solution for 1month, followed by acute ethanol administration (4.0g/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.ResultsChronic 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.ConclusionsAlcohol 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.