Quintanilla María Elena, Tampier Lutske, Sapag Amalia, Gerdtzen Ziomara, Israel Yedy
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E531-7. doi: 10.1152/ajpendo.00187.2007. Epub 2007 May 8.
Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase ("burst") with levels that were 2.5-fold greater than in males (P < 0.02). Castration of males led to 1) an increased ADH activity (+50%, P < 0.001), 2) the appearance of an acetaldehyde burst (3- to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH.NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake.
携带活性最高的乙醇脱氢酶（ADH）同工型的个体对酒精中毒具有抵抗力。这项研究探讨了高ADH活性导致动物乙醇摄入量降低的机制。雄性和雌性乙醇饮用大鼠（UChB）可饮用10%的乙醇1小时。雌性大鼠的肝脏ADH活性比雄性高70%，自愿乙醇摄入量比雄性低60%。给予乙醇（1 g/kg腹腔注射）后，雌性大鼠的血液乙醛水平出现短暂升高（“爆发”），其水平比雄性高2.5倍（P < 0.02）。阉割雄性大鼠导致：1）ADH活性增加（+50%，P < 0.001）；2）出现乙醛爆发（与假手术组相比增加3至4倍）；3）自愿乙醇摄入量减少，与未接触过乙醇的雌性大鼠相当。ADH抑制剂4-甲基吡唑可阻止动脉乙醛的出现并增加乙醇摄入量。由于从ADH·NADH复合物中释放NADH是ADH（而非ALDH2）活性的限速步骤，乙醇摄入时存在的内源性NADH氧化底物可能导致乙醛爆发。乙醇给药时给予丙酮酸钠会导致乙醛突然爆发，并使自愿乙醇摄入量大幅降低。总体而言，乙醇给药后动脉乙醛会出现短暂激增，原因是：1）ADH水平高；2）存在可氧化肝脏NADH的代谢物。乙醛爆发与乙醇摄入量的显著降低密切相关。
