Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Alcohol Clin Exp Res. 2012 Nov;36(11):1840-50. doi: 10.1111/j.1530-0277.2012.01799.x. Epub 2012 Apr 6.
Ethanol (EtOH) is metabolized by a 2-step process in which alcohol dehydrogenase (ADH) oxidizes EtOH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in EtOH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered EtOH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in EtOH metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated EtOH solution osmolarity as a potential explanation for contrasting published data on C. elegans EtOH sensitivity.
We developed a gas chromatography assay and validated a spectrophotometric method to measure internal EtOH in EtOH-exposed worms. Further, we tested the effects of mutations in ADH and ALDH genes on EtOH tissue accumulation and behavioral sensitivity to the drug. Finally, we tested the effects of EtOH solution osmolarity on behavioral responses and tissue EtOH accumulation.
Only a small amount of exogenously applied EtOH accumulated in the tissues of C. elegans and consequently their tissue concentrations were similar to those that intoxicate humans. Independent inactivation of an ADH-encoding gene (sodh-1) or an ALDH-encoding gene (alh-6 or alh-13) increased the EtOH concentration in worms and caused hypersensitivity to the acute sedative effects of EtOH on locomotion. We also found that the sensitivity to the depressive effects of EtOH on locomotion is strongly influenced by the osmolarity of the exogenous EtOH solution.
Our results indicate that EtOH metabolism via ADH and ALDH has a statistically discernable but surprisingly minor influence on EtOH sedation and internal EtOH accumulation in worms. In contrast, the osmolarity of the medium in which EtOH is delivered to the animals has a more substantial effect on the observed sensitivity to EtOH.
乙醇（EtOH）通过两步代谢过程被代谢，其中醇脱氢酶（ADH）将 EtOH 氧化为乙醛，乙醛进一步被醛脱氢酶（ALDH）氧化为乙酸盐。尽管人类乙醇代谢的变化强烈影响慢性滥用酒精的倾向，但关于改变的乙醇代谢的行为影响的数据很少。在这里，我们使用线虫秀丽隐杆线虫直接研究乙醇代谢的变化如何改变急性暴露期间对酒精的行为反应。此外，我们研究了乙醇溶液渗透压作为解释秀丽隐杆线虫乙醇敏感性的对照发表数据的潜在解释。
我们开发了一种气相色谱测定法并验证了分光光度法来测量暴露于乙醇的蠕虫中的内部乙醇。此外，我们测试了 ADH 和 ALDH 基因突变对乙醇组织积累和药物行为敏感性的影响。最后，我们测试了乙醇溶液渗透压对行为反应和组织乙醇积累的影响。
只有少量外源应用的乙醇积累在秀丽隐杆线虫的组织中，因此它们的组织浓度与使人类中毒的浓度相似。独立失活一个 ADH 编码基因（sodh-1）或一个 ALDH 编码基因（alh-6 或 alh-13）增加了蠕虫中的乙醇浓度，并导致对乙醇对运动的急性镇静作用的超敏性。我们还发现，对乙醇对运动的抑制作用的敏感性强烈受外源性乙醇溶液渗透压的影响。
我们的结果表明，通过 ADH 和 ALDH 的乙醇代谢对乙醇镇静和蠕虫内部乙醇积累具有统计学上可区分但令人惊讶的较小影响。相比之下，向动物提供乙醇的介质的渗透压对观察到的对乙醇的敏感性具有更大的影响。
