Yourick J J, Faiman M D
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Alcohol. 1987 Nov-Dec;4(6):463-7. doi: 10.1016/0741-8329(87)90086-3.
Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.
二乙基二硫代氨基甲酸甲酯（DDTC-Me）是双硫仑的主要代谢产物。给大鼠注射后，发现DDTC-Me可抑制肝脏线粒体低Km醛脱氢酶（ALDH），而对高Km同工酶无任何影响。DDTC-Me在体内对低Km ALDH的抑制呈现剂量反应关系，当以1.8至158 mg/kg的剂量腹腔注射DDTC-Me时，ALDH的抑制率为11%至90%。单次腹腔注射DDTC-Me（41.2 mg/kg）后，低Km ALDH被抑制168小时，提示为不可逆的酶抑制。对经DDTC-Me处理的大鼠进行乙醇激发后，观察到平均动脉压（MAP）降低和心率增加。乙醇激发后几乎立即出现MAP下降，并在乙醇激发后的4小时内持续处于低水平。这些结果表明，体内给予DDTC-Me可引起酒精敏感反应，并且DDTC-Me实际上可能是双硫仑产生双硫仑-乙醇反应的代谢产物。有人提出该反应应更准确地称为DDTC-Me-乙醇反应或D-MER。
