Contribution to first-pass metabolism of ethanol and inhibition by ethanol for retinol oxidation in human alcohol dehydrogenase family - Implications for etiology of fetal alcohol syndrome and alcohol-related diseases
Contribution to first-pass metabolism of ethanol and inhibition by ethanol for retinol oxidation in human alcohol dehydrogenase family - Implications for etiology of fetal alcohol syndrome and alcohol-related diseases
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DOI：
10.1046/j.1432-1327.1998.2540025.x
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发表时间：
1998-05-15
期刊：
影响因子：
--
通讯作者：
Yin, SJ
中科院分区：
文献类型：
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作者：
Han, CL;Liao, CS;Yin, SJ
乙醇脱氢酶(ADH)家族参与乙醇和维甲酸的代谢。为了定量评估乙醇对第一通道代谢的潜在贡献以及乙醇对维甲酸稳态的干扰，我们评估和比较了乙醇氧化的饱和动力学和乙醇对人I类α、β(1)β(1)、β(2)β(2)、γ(1)γ(1)、II类pi、III chi和IV类穆穆全反式视黄醇氧化的抑制动力学。I类和Il类ADHS表现出底物抑制，抑制常数在250-720 mM(伽马(1)伽马(1)除外)乙醇范围内。当乙醇浓度达到1M时，IV型ADH没有明显的抑制作用。在250 mM乙醇中检测不到Ⅲ类酶(190 nM亚基)的活性。动力学模拟表明，肝脾和胃穆穆对酒精首过代谢的贡献最大。I级、IT级和IV级ADHS中视黄醇氧化相对于乙醇氧化的米氏常数(K-m)、转化数(k(Cat))和催化效率(k(Cat)/K-m)分别在0.00022-1.30、0.071-0.48和0.24-650%之间。对于I、II和IV类ADHS，乙醇是与视黄醇竞争的抑制剂，其表观抑制常数在0.037-11 mM之间，这表明在社交/大量饮酒时，通过ADH途径合成的视黄酸可以被极大地阻止。这些发现支持酒精的首次代谢可能主要发生在肝脏中通过IIpi类pi，细胞维甲酸信号可能被乙醇通过ADH途径扰乱的观点。
The alcohol dehydrogenase (ADH) family is involved in the metabolism of both ethanol and retinoids. To quantitatively assess the potential contributions to first-pass metabolism of ethanol and the ethanol interference with retinoid homeostasis, saturation kinetics for ethanol oxidation as well as inhibition kinetics by ethanol for all-trans-retinol oxidation of human class I alpha alpha, beta(1) beta(1), beta(2) beta(2), gamma(1) gamma(1), class II pi pi, class III chi chi, and class IV mu mu were evaluated and compared. Class I and class Il ADHs exhibited substrate inhibition with inhibition constants ranging over 250-720 mM (except gamma(1) gamma(1)) ethanol. Class IV ADH displayed no appreciable inhibition up to 1 M ethanol. Activity of the class III enzyme (190 nM subunit) was undetectable at 250 mM ethanol. The kinetic simulations indicate that the hepatic pi pi and the gastric mu mu can most effectively contribute to first-pass metabolism of alcohol. The Michaelis constant (K-m), turnover number (k(cat)), and catalytic efficiency (k(cat)/K-m) for retinol oxidation relative to that for ethanol oxidation in class I, class IT, and class IV ADHs ranged over 0.00022-1.3, 0.071-0.48, and 0.24-650, respectively. Ethanol was a competitive inhibitor against retinol for class I, II, and IV ADHs with apparent inhibition constants ranging over 0.037-11 mM, indicating that retinoic acid synthesis through the ADH pathways can be tremendously blocked during social/heavy drinking. These findings support the notion that first-pass metabolism of alcohol may occur mainly in the liver through class II pi pi and that cellular retinoid signaling may be perturbed by ethanol via ADH pathways.