酒精对酒精代谢酶影响的变异性可能决定了对酒精的相对敏感性:一个新的假设。

S M Singh
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引用次数: 10

摘要

个体和种族对酒精和酒精中毒的反应差异有很强的遗传倾向。大多数关于实际遗传决定因素的研究都集中在酒精代谢主要途径的两种酶乙醇脱氢酶(ADH)和乙醛脱氢酶(ALDH)同工酶上。虽然已知在易感人群中存在这两种酶的少数“活性”变异(与结构基因突变相关),但这些观察结果并不能充分解释在人群中观察到的对酒精反应的变异性。最近的一些研究报道,在人、大鼠和小鼠中,这两种酶在暴露于酒精的不同时间长度后的特定活性发生了变化。观察到的诱导-抑制被假设是由一个或多个与两种酶的结构位点相关的诱导遗传元件(IGE)调节的。在给定水平的酒精刺激下,IGE的变异性将允许ADH和ALDH特异性活性的基因型(个体)特异性反应。考虑到该途径的主要代谢物乙醛的相对毒性,预计耐药个体会表现出ALDH诱导。相反,易感个体对酒精的反应应该是ALDH抑制。个体在饮酒后表现出诱导或抑制的能力取决于其与特定酶位点相关的IGE基因型。此外,这些位点的多态性程度预计是广泛的,但群体和种族特异性。一旦实验确定,这种方法可能在筛查、咨询、预防和新的治疗方法方面具有重要意义。
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Variability in the effect of alcohol on alcohol metabolizing enzymes may determine relative sensitivity to alcohols: a new hypothesis.

Individual and racial differences in response to alcohol and with respect to alcoholism have strong genetic predispositions. Most studies on the actual genetic determinants have concentrated on the isozymes of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), the two enzymes of the primary pathway of alcohol metabolism. Although few "activity" variants (associated with mutations in the structural genes) of the two enzymes are known to exist in susceptible groups, these observations do not offer an adequate explanation for the observed variability in response to alcohols in the population. Some recent studies have reported alterations in the specific activity of the two enzymes following exposure to alcohol for different lengths of time in man, rat, and mice. The induction-repression so observed is hypothesized to be regulated by one or more inducibility genetic elements (IGE) associated with the structural loci of the two enzymes. Variability in IGE will permit a genotype (individual) specific response in ADH and ALDH specific activity when challenged with a given level of alcohol. Considering the relative toxicity of acetaldehyde, the primary metabolite of this pathway, the resistant individuals would be expected to show ALDH induction. Conversely, the susceptible individuals should respond to alcohol by ALDH repression. The ability of an individual to show induction or repression following alcohol ingestion will depend on his or her IGE genotype(s) associated with specific enzyme loci. Also, the degree of polymorphism at these loci would be expected to be extensive and yet population and race specific. Once experimentally established, this approach could have important implications in screening, counselling, prevention, and in novel approaches to treatment.

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