A new view of alcohol metabolism and alcoholism--role of the high-Km Class III alcohol dehydrogenase (ADH3).
A new view of alcohol metabolism and alcoholism--role of the high-Km Class III alcohol dehydrogenase (ADH3).
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DOI：
10.3390/ijerph7031076
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发表时间：
2010-03
影响因子：
--
通讯作者：
Ohno Y
中科院分区：
文献类型：
--
作者：
Haseba T;Ohno Y
传统观点认为，酒精代谢是由肝脏中的ADH1（I类）进行的。然而，有人提出，另一种途径在酒精代谢中发挥着重要作用，尤其是当血液乙醇水平较高或长期饮酒时。在过去的三十年里，人们大力尝试鉴定负责非 ADH1 途径的酶，重点关注微粒体乙醇氧化系统 (MEOS) 和过氧化氢酶，但未能阐明它们在全身酒精代谢中的作用。最近，使用ADH3缺失突变小鼠，我们证明ADH3（III类）具有高Km，是一种古老起源的普遍酶，以剂量依赖性方式促进全身酒精代谢，从而减少急性酒精中毒。尽管由于其极高的 Km，ADH3 在体外对乙醇的活性通常较低，但当反应介质的溶液疏水性增加时，催化效率 (kcat/Km) 显着增强。通过增加疏水性来激活 ADH3 也应该发生在肝细胞中；当使用尼罗红作为疏水性探针时，小鼠肝细胞的细胞质溶液比缓冲溶液具有更强的疏水性。当给小鼠注射不同剂量的乙醇时，肝脏 ADH3 活性通过诱导或动力学激活进行动态调节，而高剂量（3-5 g/kg）时 ADH1 活性显着降低。这些数据表明 ADH3 在酒精代谢中发挥着动态作用，要么与 ADH1 协同作用，要么补偿 ADH1 作用的减弱。将总肝脏 ADH 活性归因于 ADH1 和 ADH3 的复杂双 ADH 模型很好地解释了血液乙醇的药代动力学参数（β、CLT、AUC）的剂量依赖性变化，表明小鼠的酒精代谢主要由这两种 ADH 控制。在酒精性肝病患者中，随着酒精摄入量的增加，肝脏 ADH3 活性增加，而 ADH1 活性降低。此外，ADH3 在疏水性较高的受损细胞中被诱导，而当存在严重肝脏疾病时，ADH1 活性较低。这些数据表明，长期酗酒和由此产生的肝脏疾病会将酒精代谢中的关键酶从低 Km ADH1 转移到高 Km ADH3，从而降低酒精代谢率。 ADH3/ADH1 活性比值和 AUC 的相互依赖的增加可能是酒精性肝病发生的一个因素。然而，ADH3的适应性增加维持了酒精代谢，即使是酒精性肝硬化患者，这也使他们有可能酗酒致死。因此，ADH3 活性的调节对于预防酒精中毒的发展可能很重要。
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.
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DOI：
10.1073/pnas.82.24.8369
发表时间：
1985-12-01
影响因子：
11.1
作者：
BEISSWENGER, TB;HOLMQUIST, B;VALLEE, BL
通讯作者：
VALLEE, BL
DOI：
10.1111/j.1432-1033.1993.tb18059.x
发表时间：
1993-07-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ESTONIUS, M;DANIELSSON, O;HOOG, JO
通讯作者：
HOOG, JO
DOI：
10.1111/j.1432-1033.1983.tb07807.x
发表时间：
1983-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ALGAR, EM;SEELEY, TL;HOLMES, RS
通讯作者：
HOLMES, RS
DOI：
10.1111/j.1530-0277.1978.tb04748.x
发表时间：
1978-01-01
影响因子：
3.2
作者：
FEINMAN, L;BARAONA, E;LIEBER, CS
通讯作者：
LIEBER, CS
DOI：
10.1046/j.1432-1327.1998.2540025.x
发表时间：
1998-05-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Han, CL;Liao, CS;Yin, SJ
通讯作者：
Yin, SJ