Yourick J J, Faiman M D
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045.
Biochem Pharmacol. 1991 Sep 12;42(7):1361-6. doi: 10.1016/0006-2952(91)90446-c.
In humans and animals, disulfiram produces a disulfiram-ethanol reaction after an ethanol challenge, the basis of which is the inhibition of liver aldehyde dehydrogenase (ALDH). Disulfiram and the metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl-N,N-diethylthiolcarbamate (DETC-Me) were studied in order to determine the role of bioactivation in disulfiram's action as an inhibitor of rat liver mitochondrial low Km ALDH (RLM low Km ALDH). In in vitro studies, disulfiram and DDTC (0.01 to 2.0 mM) both inhibited RLM low Km ALDH in a concentration-dependent manner. The addition of rat liver microsomes to the mitochondrial incubation did not further increase disulfiram-induced RLM low Km ALDH inhibition. However, DDTC-induced RLM low Km ALDH inhibition was increased further, but only at DDTC concentrations less than 0.05 mM. DDTC-Me and DETC-Me (2.0 mM) similarly exhibited an increased RLM low Km ALDH inhibition after the addition of liver microsomes. In in vivo studies, disulfiram (75 mg/kg), DDTC (114 mg/kg), DDTC-Me (41.2 mg/kg) or DETC-Me (18.6 mg/kg) administered i.p. to female rats inhibited RLM low Km ALDH. Inhibition of drug metabolism by pretreatment of rats with the cytochrome P450 inhibitor N-octylimidazole (NOI) (20 mg/kg, i.p.) prior to either disulfiram, DDTC, DDTC-Me or DETC-Me administration blocked the inhibition of RLM low Km ALDH. The in vitro and in vivo data support the conclusion that bioactivation of disulfiram to a reactive chemical species is required for RLM low Km ALDH inhibition and a disulfiram-ethanol reaction.
在人类和动物中，双硫仑在乙醇激发后会产生双硫仑-乙醇反应，其基础是对肝脏醛脱氢酶（ALDH）的抑制。对双硫仑及其代谢产物二乙二硫代氨基甲酸盐（DDTC）、二乙二硫代氨基甲酸盐甲酯（DDTC-Me）和S-甲基-N,N-二乙硫代氨基甲酸盐（DETC-Me）进行了研究，以确定生物活化在双硫仑作为大鼠肝脏线粒体低Km ALDH（RLM低Km ALDH）抑制剂作用中的作用。在体外研究中，双硫仑和DDTC（0.01至2.0 mM）均以浓度依赖性方式抑制RLM低Km ALDH。将大鼠肝脏微粒体添加到线粒体孵育体系中，并不会进一步增强双硫仑诱导的RLM低Km ALDH抑制作用。然而，DDTC诱导的RLM低Km ALDH抑制作用会进一步增强，但仅在DDTC浓度低于0.05 mM时出现。添加肝脏微粒体后，DDTC-Me和DETC-Me（2.0 mM）同样表现出RLM低Km ALDH抑制作用增强。在体内研究中，对雌性大鼠腹腔注射双硫仑（75 mg/kg）、DDTC（114 mg/kg）、DDTC-Me（41.2 mg/kg）或DETC-Me（18.6 mg/kg）均可抑制RLM低Km ALDH。在给予双硫仑、DDTC、DDTC-Me或DETC-Me之前，先用细胞色素P450抑制剂N-辛基咪唑（NOI）（20 mg/kg，腹腔注射）预处理大鼠以抑制药物代谢，可阻断RLM低Km ALDH的抑制作用。体外和体内数据均支持以下结论：双硫仑生物活化生成反应性化学物质是抑制RLM低Km ALDH和发生双硫仑-乙醇反应所必需的。
