Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse
Dose-Dependent Change in Elimination Kinetics of Ethanol due to Shift of Dominant Metabolizing Enzyme from ADH 1 (Class I) to ADH 3 (Class III) in Mouse
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DOI：
10.1155/2012/408190
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发表时间：
2012-01-01
影响因子：
1.8
通讯作者：
Ohno, Youkichi
中科院分区：
文献类型：
--
作者：
Haseba, Takeshi;Kameyama, Kouji;Ohno, Youkichi
ADH-1和ADH-3是肝脏中主要的两种ADH同工酶，参与全身性酒精代谢，主要分布于肝实质和肝窦内皮细胞。我们通过给小鼠灌胃不同剂量的乙醇，并通过测量两种ADH的肝脏ADH活性和肝脏内容物，研究了这两种ADH对血液乙醇消除动力学的贡献。标准化AUC(AUC/剂量)随乙醇剂量的增加呈凹形增加，与β呈负相关。CLT(剂量/AUC)与肝脏ADH活性、ADH-1和-3含量(mg/kg bw.)呈线性相关。当ADH-1活性以ADH-1含量乘以其V-max/mg(4.0)并以各乙醇剂量的肝脏ADH活性与对照组的比率归一化时，理论ADH-1活性随剂量的增加而降低，且与β相关。另一方面，理论ADH-3活性由肝脏ADH活性减去ADH-1活性计算得出，并随剂量增加而增加，与归一化AUC相关。这些结果表明，小鼠血液中乙醇的消除动力学随剂量的变化而改变，并伴随着主要代谢酶由ADH-1向ADH-3的转移。
ADH 1 and ADH 3 are major two ADH isozymes in the liver, which participate in systemic alcohol metabolism, mainly distributing in parenchymal and in sinusoidal endothelial cells of the liver, respectively. We investigated how these two ADHs contribute to the elimination kinetics of blood ethanol by administering ethanol to mice at various doses, and by measuring liver ADH activity and liver contents of both ADHs. The normalized AUC (AUC/dose) showed a concave increase with an increase in ethanol dose, inversely correlating with beta. CLT (dose/AUC) linearly correlated with liver ADH activity and also with both the ADH-1 and -3 contents (mg/kg B.W.). When ADH-1 activity was calculated by multiplying ADH-1 content by its V-max/mg (4.0) and normalized by the ratio of liver ADH activity of each ethanol dose to that of the control, the theoretical ADH-1 activity decreased dose-dependently, correlating with beta. On the other hand, the theoretical ADH-3 activity, which was calculated by subtracting ADH-1 activity from liver ADH activity and normalized, increased dose-dependently, correlating with the normalized AUC. These results suggested that the elimination kinetics of blood ethanol in mice was dose-dependently changed, accompanied by a shift of the dominant metabolizing enzyme from ADH 1 to ADH 3.