Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking
Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking
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DOI：
10.15288/jsa.2000.61.5
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Li, TK
中科院分区：
文献类型：
--
作者：
Li, TK
目的：现在有令人信服的证据表明遗传因素对酒精中毒的易感性有影响。本文介绍了从研究结果资格酗酒作为一种药物遗传性疾病的大脑。方法：对作者所在课题组和其他研究者在人体和实验动物模型上的研究进行综述。包括乙醇的药物遗传学（消除和代谢）和药效学（初始反应，耐受性和依赖性）实验。结果如下：对人类的研究已经可靠地表明，酒精代谢的主要酶的基因影响饮酒行为和酒精中毒风险。值得注意的是，表现出高醇氧化活性的醇脱氢酶的功能性遗传变体和表现出低乙醛氧化活性的醛脱氢酶的通用变体防止大量饮酒和酒精中毒。对具有饮酒偏好、耐受性发展和酒精戒断易感性的近交和选择性繁殖实验啮齿动物模型的广泛研究表明，这些对乙醇的反应具有强烈的遗传影响。神经解剖学、神经化学和遗传学研究表明，乙醇的这些作用涉及5-羟色胺、多巴胺、谷氨酸、γ-氨基丁酸和阿片途径。遗传学研究，包括人类和啮齿动物的关联和全基因组调查研究，表明5-羟色胺Ib受体、多巴胺D2受体、色氨酸羟化酶和神经肽Y是乙醇这些药效学作用中遗传易感性的候选靶点。结论：酒精中毒存在遗传易感因素。非特异性易感性因素包括以行为抑制为特征的人格特征（例如，追求新奇和冲动）。这些受遗传影响的性状与其他也受遗传影响的、参与酒精代谢和药效学效应的性状相互作用，这种相互作用形成了将酒精中毒命名为药物遗传学疾病的基础。显然，还有许多环境因素影响饮酒行为。个体具有不同的易感基因组，并经历不同类型的环境刺激。这些因素构成了酒精中毒临床表型的异质性和复杂性。
Objective: There is now compelling evidence for genetic influence on susceptibility to alcoholism. This article presents results from studies qualifying alcoholism as a pharmacogenetic disorder of the brain. Method: Studies from the author's research group and other investigators, of human subjects and experimental animal models, are reviewed. Included are experiments on the pharmacogenetics (elimination and metabolism) and pharmacodynamics (initial response, tolerance and dependence) of ethanol. Results: Studies in humans have reliably shown that the genes for the principal enzymes of alcohol metabolism influence drinking behavior and alcoholism risk. Notably, the functional genetic variants of alcohol dehydrogenase that exhibit high alcohol oxidizing activity, and the generic variant of aldehyde dehydrogenase that exhibits low acetaldehyde oxidizing activity, protect against heavy drinking and alcoholism. Extensive studies of inbred and selectively bred experimental rodent models with alcohol drinking preference, tolerance development and alcohol withdrawal susceptibility have shown strong genetic influence on these responses to ethanol. Neuroanatomical, neurochemical and genetic studies have shown the involvement of serotonin, dopamine, glutamate, gamma-aminobutyric acid and opioid pathways in these actions of ethanol. Genetic studies, including association and genome-wide survey studies in both humans and rodents, implicate serotonin Ib receptor, dopamine D2 receptor, tryptophan hydroxylase and neuropeptide Y as candidate targets of genetic susceptibility in these pharmacodynamic actions of ethanol. Conclusions: There are genetic predisposing factors for alcoholism. Nonspecific Susceptibility factors include personality traits characterized by behavioral inhibition (e.g., novelty-seeking and impulsivity). These genetically influenced traits interact with other, also genetically influenced, traits involved in the metabolism and pharmacodynamic effects of alcohol, and this interaction forms the basis for nominating alcoholism as a pharmacogenetic disease. Clearly, there are also many environmental factors that influence drinking behavior. Individuals have different sets of susceptibility genes and experience different kinds of environmental provocation. These factors underlie the heterogeneity and complexity of the clinical phenotype of alcoholism.