S-methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram.
S-methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram.
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S-甲基-N,N-二乙基硫代氨基甲酸酯亚砜和S-甲基-N,N-二乙基硫代氨基甲酸酯砜是双硫仑活性代谢物的两种候选物。
DOI：
10.1111/j.1530-0277.1996.tb01099.x
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Lipsky,JJ
中科院分区：
文献类型：
--
作者：
Mays,DC;Nelson,AN;Lam-Holt,J;Fauq,AH;Lipsky,JJ
双硫仑的作用机制涉及抑制肝醛脱氢酶（ALDH）。尽管双硫仑在体外抑制 ALDH，但人们认为该药物在体内的寿命太短，无法直接抑制该酶。最终的抑制剂被认为是双硫仑的代谢物。在本研究中，我们研究了 S-甲基-N,N-二乙基硫代氨基甲酸酯 (MeDTC) 亚砜和 S-甲基-N,N-二乙基硫代氨基甲酸酯砜（分别为双硫仑的已确认和拟议代谢物）对大鼠肝线粒体 lowKmALDH 的影响。 MeDTC 亚砜和 MeDTC 砜与去污剂溶解的线粒体一起孵育 10 分钟，抑制 ALDH 活性，IC50（平均值±标准差）分别为 0.93 ± 0.04 和 0.53 ± 0.11 μM，而母药双硫仑的 IC50（平均值 ± SD）为 7.4 ± 1.0 μM。 MeDTC 砜和 MeDTC 亚砜的抑制作用均为 0.6 μM，具有时间依赖性，遵循明显的伪一级动力学，at1/2of 失活时间分别为 3.5 分钟和 8.8 分钟。亚砜或砜抑制的 ALDH 的稀释不会恢复活性，这表明存在不可逆的抑制。在抑制剂之前向 ALDH 添加谷胱甘肽（50 至 1000 μM）不会改变 MeDTC 亚砜的抑制作用。相比之下，50 μM 谷胱甘肽对 MeDTC 砜的抑制作用降低了 10 倍以上（IC50= 6.3 μM），而 500 μM 谷胱甘肽几乎完全消除了这种抑制作用。辅因子 NAD 以浓度依赖性方式保护 ALDH 免受 MeDTC 亚砜和 MeDTC 砜的抑制。在与完整线粒体一起孵育时，两种化合物的效力发生逆转（MeDTC 砜和亚砜的 IC50 分别为 9.2 ± 3.6 和 0.95 ± 0.30 μM）。我们的结果表明，MeDTC 砜与正常细胞成分（例如谷胱甘肽）具有高度反应性，这可以保护 ALDH 免受抑制，除非该抑制剂形成于非常靠近目标酶的位置。相比之下，MeDTC 亚砜是双硫仑最终活性代谢物的更好候选者，因为它更有可能足够稳定，能够从较远的形成位点（例如内质网）扩散，穿透线粒体，并与位于线粒体基质中的 ALDH 发生反应。
The mechanism of action of disulfiram involves inhibition of hepatic aldehyde dehydrogenase (ALDH). Although disulfiram inhibits ALDH in vitro, it is believed that the drug is too short‐lived in vivo to inhibit the enzyme directly. The ultimate inhibitor is thought to be a metabolite of disulfiram. In this study, we examined the effects ofS‐methyl‐N,N‐diethylthiocarbamate (MeDTC) sulfoxide andS‐methyl‐N,N‐diethylthiocarbamate sulfone (confirmed and proposed metabolites of disulfiram, respectively) on rat liver mitochondrial lowKmALDH. MeDTC sulfoxide and MeDTC sulfone, in 10‐min incubations with detergent‐solubilized mitochondria, inhibited ALDH activity with an IC50(mean ± SD) of 0.93 ± 0.04 and 0.53 ± 0.11 μM, respectively, compared with 7.4 ± 1.0 μM for the parent drug disulfiram. Inhibition by MeDTC sulfone and MeDTC sulfoxide, both at 0.6 μM, was time‐dependent, following apparent pseudo‐first‐order kinetics with at1/2of inactivation of 3.5 and 8.8 min, respectively. Dilution of ALDH inhibited by either sulfoxide or sulfone did not restore activity, an indication of irreversible inhibition. Addition of glutathione (50 to 1000 μM) to ALDH before the inhibitors did not alter the inhibition by MeDTC sulfoxide. In contrast, the inhibition by MeDTC sulfone was decreased > 10‐fold (IC50= 6.3 μM) by 50 μM of glutathione and almost completely abolished by 500 μM of glutathione. The cofactor NAD, in a concentration‐dependent manner, protected ALDH from inhibition by MeDTC sulfoxide and MeDTC sulfone. In incubations with intact mitochondria, the potency of the two compounds was reversed (IC50of 9.2 ± 3.6 and 0.95 ± 0.30 μM for the MeDTC sulfone and sulfoxide, respectively). Our results suggest that MeDTC sulfone is highly reactive with normal cellular constituents (e.g., glutathione), which may protect ALDH from inhibition, unless this inhibitor is formed very near the target enzyme. In contrast, MeDTC sulfoxide is a better candidate for the ultimate active metabolite of disulfiram, because it is more likely to be sufficiently stable to diffuse from a distant site of formation, such as the endoplasmic reticulum, penetrate the mitochondria, and react with ALDH located in the mitochondrial matrix.
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双硫仑和二乙基二硫代氨基甲酸酯体内抑制乙醛脱氢酶的机制。
影响因子：
3.6
作者：
R. Deitrich;V. Erwin
通讯作者：
V. Erwin
影响因子：
5.8
作者：
MAYS, DC;NELSON, AN;LIPSKY, JJ
通讯作者：
LIPSKY, JJ
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影响因子：
2.9
作者：
Wiseman,JS;Tayrien,G;Abeles,RH
通讯作者：
Abeles,RH
影响因子：
5.8
作者：
MADAN, A;PARKINSON, A;FAIMAN, MD
通讯作者：
FAIMAN, MD
双硫仑-乙醇反应：综述。
DOI：
--
发表时间：
1977
期刊：
Journal of Studies on Alcohol
影响因子：
--
作者：
T. Kitson
通讯作者：
T. Kitson