In vivo pharmacodynamic studies of the disulfiram metabolite S-methyl N,N-diethylthiolcarbamate sulfoxide: inhibition of liver aldehyde dehydrogenase.
In vivo pharmacodynamic studies of the disulfiram metabolite S-methyl N,N-diethylthiolcarbamate sulfoxide: inhibition of liver aldehyde dehydrogenase.
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双硫仑代谢物 S-甲基 N,N-二乙基硫醇氨基甲酸酯亚砜的体内药效学研究：抑制肝醛脱氢酶。
DOI：
10.1111/j.1530-0277.1994.tb00023.x
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发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Faiman,MD
中科院分区：
文献类型：
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作者：
Hart,BW;Faiman,MD
S-甲基 N,N-二乙基硫醇氨基甲酸酯亚砜 (DETC-MeSO) 被认为是双硫仑的代谢产物，负责体内抑制大鼠肝脏低 Km 乙醛脱氢酶 (ALDH)。在雄性 Sprague-Dawley 大鼠中进行了研究，并在体外使用大鼠肝线粒体和纯化的牛线粒体低 KmALDH 进行了研究，以进一步研究 DETC-MeSO 的药效和药代动力学特征。给予大鼠 DETC-MeSO 在 2 小时内对肝线粒体低 Km、ALDH 产生快速和最大程度的抑制，168 小时后仍抑制 30%。 DETC-MeSO 处理后，DETC-MeSO 的最大血浆浓度在 0.5 小时内达到，DETC-MeSO 给药后 2 小时检测不到 DETC-MeSO。尽管在给大鼠施用 DETC-MeSO 0.5 小时后，血浆中检测到微量 DETC-Me，但这种情况在 1 小时内消失。当大鼠接受双硫仑治疗时，DETC-MeSO 在 2 小时内达到最大血浆浓度，8 小时后仅可检测到极少量的 DETC-MeSO。还给予大鼠双硫仑代谢物二乙基二硫代氨基甲酸酯 (DDTC)、二乙基二硫代氨基甲酸酯甲酯 (DDTC-Me) 和 S-甲基 N,N-二乙基硫醇氨基甲酸酯 (DETC-Me)，并在给予这些代谢物 2 小时后对血浆进行 DETC-MeSO 分析。在血浆中检测到 DETC-MeSO，进一步说明在服用双硫仑或随后的体内代谢物 DDTC、DDTC-Me 或 DETC-Me 后，可以在血浆中发现 DETC-MeSO。用 DETC-MeSO 处理然后用乙醇攻击的大鼠表现出血液乙醛含量增加，与之前使用双硫仑的研究发现的结果相似。在体外研究中，将大鼠肝线粒体与 0.75 μM DETC-MeSO 一起孵育，在 2 小时内最大程度地抑制大鼠肝线粒体低 KmALDH，而当与 2 和 6 μM DETC-MeSO 一起孵育 1 小时时，纯化的牛线粒体低 KmALDH 分别被抑制 90% 和 99%。这些对大鼠和纯化牛 ALDH 的研究表明，DETC-MeSO 在体内和体外都是线粒体低 KmALDH 的有效抑制剂，这提供了额外的证据，证明 DETC-MeSO 是双硫仑必须被生物激活才能抑制肝脏 ALDH 的代谢物。
S‐methyl N,N‐diethylthiolcarbamate sulfoxide (DETC‐MeSO) is proposed to be the metabolite of disulfiram responsible for the in vivo inhibition of liver low Km, aldehyde dehydrogenase (ALDH) in the rat. Studies were conducted in male Sprague‐Dawley rats and also in vitro using both rat liver mitochondrial and purified bovine mitochondrial low KmALDH to investigate further the pharmacodynamic and pharmacokinetic characteristics of DETC‐MeSO. Administration of DETC‐MeSO to rats produced a rapid and maximal inhibition of liver mitochondrial low Km, ALDH within 2 hr, which was still inhibited 30% after 168 hr. After DETC‐MeSO treatment, the maximum plasma concentration of DETC‐MeSO was reached within 0.5 hr, with DETC‐MeSO being undetectable 2 hr after DETC‐MeSO dosing. Although a trace amount of DETC‐Me was detected in the plasma 0.5 hr after DETC‐MeSO administration to rats, this disappeared within 1 hr. When rats were treated with disulfiram, the maximal plasma concentration of DETC‐MeSO was found within 2 hr, with only a very small quantity of DETC‐MeSO still detectable after 8 hr. Rats also were given the disulfiram metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate‐methyl ester (DDTC‐Me), and S‐methyl N,N‐diethylthiolcarbamate (DETC‐Me), and plasma analyzed for DETC‐MeSO 2 hr after the administration of these metabolites. DETC‐MeSO was detected in plasma, further illustrating that DETC‐MeSO can be found in plasma after the administration of either disulfiram, or the subsequent in vivo metabolites DDTC, DDTC‐Me, or DETC‐Me. Rats treated with DETC‐MeSO and then challenged with ethanol exhibited an increase in blood acetaldehyde similar to that found from previous studies with disulfiram. In in vitro studies, incubation of rat liver mitochondria with 0.75 μM DETC‐MeSO inhibited rat liver mitochondrial low KmALDH maximally within 2 hr, whereas purified bovine mitochondrial low KmALDH was inhibited 90% and 99%, respectively, when incubated for 1 hr with 2 and 6 μM DETC‐MeSO. These studies with rats and purified bovine ALDH show that DETC‐MeSO is a potent inhibitor of mitochondrial low KmALDH both in vivo and in vitro, providing additional evidence that DETC‐MeSO is the metabolite to which disulfiram must be bioactivated for liver ALDH to be inhibited.