meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent.
meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent.
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DOI：
10.1146/annurev.pa.30.040190.001431
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发表时间：
1990
影响因子：
12.5
通讯作者：
H. Aposhian;M. Aposhian
中科院分区：
文献类型：
--
作者：
H. Aposhian;M. Aposhian
本文的主要目的是总结最近有关内消旋-2，3-二巯基琥珀酸（一种口服有效螯合剂）药理学和毒理学的研究。需要一种更好的螯合剂来治疗幼儿和孕妇的铅中毒已经有一段时间了。临床前和临床证据现在表明，内消旋-2，3-二巯基琥珀酸，一种孤儿药，在这方面显示出最有效的前景。它具有细胞外分布，这可能是与其他二硫醇相比其毒性低的原因。没有尝试以严格和彻底的方式将其与其他螯合剂进行比较。这不是这次审查的目的。然而，与CaNa 2 EDTA相比，meso-DMSA用于治疗铅中毒的优点已经概述。近年来，DMSA金属螯合物的结构研究取得了重大进展。外消旋DMSA和meso-DMSA的铅螯合物的结构有很大的不同。前者通过一个硫原子和一个氧原子与Pb配位而形成螯合物。后者可以通过两个硫原子或通过一个氧和一个硫原子形成螯合物。铅螯合物的溶解度取决于非配位的硫醇和羧酸基团的电离。生物体液中DMSA的分析可采用双满衍生法、高效液相色谱法、荧光法和气相色谱法。内消旋和外消旋-DMSA的酸解离常数已经从文献中总结，因为一些DMSA螯合物的形成常数也是如此。DMSA在人体内生物转化为混合二硫化物。DMSA给药（10 mg/kg）后14 h，仅2.5%的DMSA以未改变的DMSA形式经尿液排泄，18.1%的剂量以改变形式的DMSA形式经尿液排泄。尿液中大多数改变的DMSA是以混合二硫化物的形式存在。它由二硫键中的DMSA和两个L-半胱氨酸分子组成。一个半胱氨酸分子连接到DMSA的每个硫原子上。其余10%的改变的DMSA是DMSA的环状二硫化物的形式。到目前为止，已在人体中发现了混合二硫化物，但未在兔、小鼠或大鼠尿液中发现。显然，生物体如何代谢meso-DMSA存在物种差异。（400字处截断摘要）
The primary purpose of this article is to summarize the recent investigations dealing with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally effective chelating agent. The need for a better chelating agent for treating young children and pregnant women with lead intoxication has been apparent for some time. Preclinical and clinical evidence now indicate that meso-2,3-dimercaptosuccinic acid, an Orphan Drug, shows the most promise for being effective in this regard. It has an extracellular distribution that may be responsible for its low toxicity compared to other dithiols. No attempt has been made to compare it in a rigorous and thorough manner with other chelating agents. That has not been the purpose of this review. The advantages of meso-DMSA, however, compared to CaNa2EDTA for the treatment of lead intoxication, have been outlined. Significant advances have been made recently in elucidating the structures of the metal chelates of DMSA. There is a striking difference between the structures of the lead chelate of meso-DMSA and those of racemic-DMSA. The former chelates by coordination of one sulfur and one oxygen atom with Pb. The latter can form chelates via the two sulfur atoms or via one oxygen and one sulfur atom. Solubility of the lead chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups. Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and racemic-DMSA have been summarized from the literature as have the formation constants of some of the DMSA chelates. DMSA is biotransformed to a mixed disulfide in humans. By 14 hr after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide. It consists of DMSA in disulfide linkages with two molecules of L-cysteine. One molecule of cysteine is attached to each of the sulfur atoms of DMSA. The remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far, the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine. Apparently there are species differences in how organisms metabolize meso-DMSA.(ABSTRACT TRUNCATED AT 400 WORDS)