Laboratory of Gene Therapy, Department of Pharmacological and Toxicological Chemistry, University of Chile, Olivos 1007, Independencia, Santiago, Chile.
FASEB J. 2010 Jan;24(1):266-74. doi: 10.1096/fj.09-132563. Epub 2009 Aug 26.
Humans who carry a point mutation in the gene coding for alcohol dehydrogenase-1B (ADH1B2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100-fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild-type rat cDNA encoding rADH-47Arg was mutated to encode rADH-47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol-preferring rats. The V(max) of rADH-47His was 6-fold higher (P<0.001) than that of the wild-type rADH-47Arg. Animals transduced with rAdh-47His showed a 90% (P<0.01) increase in liver ADH activity and a 50% reduction (P<0.001) in voluntary ethanol intake. In animals transduced with rAdh-47His, administration of ethanol (1g/kg) produced a short-lived increase of arterial blood acetaldehyde concentration to levels that were 3.5- to 5-fold greater than those in animals transduced with the wild-type rAdh-47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B2 allele are protected against alcoholism.
携带编码醇脱氢酶-1B（ADH1B2；Arg47His）的基因突变的人对酒精中毒有明显的保护作用。尽管这种突变导致酶活性增加了 100 倍，但它并没有导致更高水平的乙醛，乙醛是乙醇的一种代谢物，已知会阻止饮酒。因此，这种突变赋予对酒精中毒的保护作用的机制尚不清楚。为了研究这种保护作用，将编码 rADH-47Arg 的野生型大鼠 cDNA 突变为编码 rADH-47His，模拟人类突变。突变 cDNA 被整合到腺病毒载体中，并施用于遗传选择的酒精偏好大鼠。rADH-47His 的 Vmax 比野生型 rADH-47Arg 高 6 倍（P<0.001）。转导 rAdh-47His 的动物的肝 ADH 活性增加了 90%（P<0.01），而自愿摄入乙醇的量减少了 50%（P<0.001）。在转导 rAdh-47His 的动物中，给予乙醇（1g/kg）会短暂增加动脉血乙醛浓度，使其达到比转导野生型 rAdh-47Arg 载体或非编码载体的动物高 3.5-5 倍的水平。在摄入乙醇后，动脉乙醛浓度的短暂增加（爆发）可能构成携带 ADH1B2 等位基因的人免受酒精中毒的机制。
