Müller L, Menzel H
Institute of Toxicology, University of Düsseldorf, F.R.G.
Biochim Biophys Acta. 1990 May 22;1052(3):386-91. doi: 10.1016/0167-4889(90)90147-6.
Lipoate (thioctic acid) is presently used in therapy of a variety of diseases such as liver and neurological disorders. However, nothing is known about the efficacy of lipoate and its reduced form dihydrolipoate in acute cadmium (Cd2+) toxicity which involves severe liver disturbances. Therefore, we investigated the effects of these redox compounds on Cd2(+)-induced injuries in isolated rat hepatocytes. The cells were coincubated with 150 microM Cd2+ and either 1.5-6.0 mM lipoate or 17-89 microM dihydrolipoate for up to 90 min and Cd2+ uptake as well as viability criteria were monitored. Both exposure regimens diminished Cd2+ uptake in correspondence to time and concentration. They also ameliorated Cd2(+)-induced cell deterioration as reflected by the decrease in Cd2(+)-induced membrane damage (leakage of aspartate aminotransferase), by the lessening of the Cd2(+)-stimulated lipid peroxidation (TBA-reactants) and by the increase in Cd2(+)-depleted cellular glutathione (GSH + 2 GSSG). Half-maximal protection was achieved at molar ratios of 9.9 to 19 (lipoate vs. Cd2+) and 0.25 to 0.74 (dihydrolipoate vs. Cd2+), indicating a 19.5 to 50.6 lower protective efficacy of lipoate as compared to dihydrolipoate. Lipoate induced an increase in extracellular acid-soluble thiols different from glutathione. It is suggested that dihydrolipoate primarily protects cells by extracellular chelation of Cd2+, whereas intracellular reduction of lipoate to the dihydro-compound followed by complexation of both intra- and extracellular Cd2+ contributes to the amelioration provided by lipoate.
硫辛酸目前用于治疗多种疾病，如肝脏疾病和神经系统疾病。然而，关于硫辛酸及其还原形式二氢硫辛酸在急性镉（Cd2+）毒性（涉及严重肝脏紊乱）中的功效尚无任何了解。因此，我们研究了这些氧化还原化合物对分离的大鼠肝细胞中Cd2+诱导损伤的影响。将细胞与150微摩尔/升的Cd2+以及1.5 - 6.0毫摩尔/升的硫辛酸或17 - 89微摩尔/升的二氢硫辛酸共同孵育长达90分钟，并监测Cd2+摄取以及活力指标。两种暴露方案均随时间和浓度降低了Cd2+摄取。它们还改善了Cd2+诱导的细胞恶化，这表现为Cd2+诱导的膜损伤（天冬氨酸转氨酶泄漏）减少、Cd2+刺激的脂质过氧化（硫代巴比妥酸反应物）减轻以及Cd2+耗尽的细胞内谷胱甘肽（GSH + 2 GSSG）增加。在摩尔比为9.9至19（硫辛酸与Cd2+）和0.25至0.74（二氢硫辛酸与Cd2+）时达到半数最大保护，表明与二氢硫辛酸相比，硫辛酸的保护功效低19.5至50.6倍。硫辛酸诱导了不同于谷胱甘肽的细胞外酸溶性硫醇增加。有人提出，二氢硫辛酸主要通过细胞外螯合Cd2+来保护细胞，而硫辛酸在细胞内还原为二氢化合物，随后细胞内和细胞外的Cd2+均形成络合物，这有助于硫辛酸提供的改善作用。
