Chen W S, Bohlken D P, Plapp B V
Adv Exp Med Biol. 1980;132:129-35. doi: 10.1007/978-1-4757-1419-7_14.
In order to decrease the rate of ethanol metabolism for the treatment of acute and chronic alcoholism it would be useful to inhibit liver alcohol dehydrogenase in vivo. Based on a knowledge of the three-dimensional structure of the horse enzyme, we designed active-site-directed inactivators [p-(XCH2CONH)C6H4(CH2)3COHN2] which bind to the enzyme-NAD or enzyme-NADH complex and alkylate methionine residue 306. In vitro, these reagents inactivated mouse, rat, horse and human liver alcohol dehydrogenases faster in the presence than in the absence of NAD or NADH, but with slightly different specificity. Mice and rats pretreated with the reagents eliminated ethanol in blood more slowly than those not treated, and the specific activity of alcohol dehydrogenase in liver homogenates of treated animals was decreased. It appears that the design of active-site-directed reagents is feasible, but these reagents must be improved so that they are more efficacious in vivo.
为了降低乙醇代谢速率以治疗急慢性酒精中毒，在体内抑制肝脏乙醇脱氢酶将是有用的。基于对马酶三维结构的了解，我们设计了活性位点导向的失活剂[p-(XCH2CONH)C6H4(CH2)3COHN2]，它与酶-NAD或酶-NADH复合物结合并使甲硫氨酸残基306烷基化。在体外，这些试剂在有NAD或NADH存在时比不存在时更快地使小鼠、大鼠、马和人肝脏乙醇脱氢酶失活，但特异性略有不同。用这些试剂预处理的小鼠和大鼠清除血液中乙醇的速度比未处理的慢，并且处理动物肝脏匀浆中乙醇脱氢酶的比活性降低。看来活性位点导向试剂的设计是可行的，但这些试剂必须改进，以便它们在体内更有效。
