Roy S, Sen C K, Tritschler H J, Packer L
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, U.S.A.
Biochem Pharmacol. 1997 Feb 7;53(3):393-9. doi: 10.1016/s0006-2952(96)00764-2.
The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.
就α-硫辛酸（硫辛酸）对细胞还原当量稳态的影响而言，对其治疗潜力进行了评估。在各种细胞和组织中，已有报道称在细胞将α-硫辛酸还原为二氢硫辛酸的过程中，需要NADH和NADPH作为辅助因子。然而，尚无直接证据描述α-硫辛酸的这种还原对细胞还原当量水平以及NAD(P)H/NAD(P)比值稳态的影响。用0.5 mM α-硫辛酸处理人类维尔茨堡T细胞系24小时后，细胞内NADH水平降低了30%。α-硫辛酸处理也降低了细胞内NADPH水平，但与NADH相比，这种影响相对较小且较慢。在用α-硫辛酸处理的维尔茨堡细胞中，观察到葡萄糖摄取呈浓度依赖性增加。在用α-硫辛酸处理的细胞中，细胞内NADH/NAD⁺和乳酸/丙酮酸比值平行下降（30%）。用α-硫辛酸处理后NADH/NAD⁺比值的这种下降可能对糖尿病、缺血再灌注损伤以及其他病理情况有直接影响，在这些病理情况中，还原（高NADH/NAD⁺比值）和氧化（过量活性氧）失衡被认为是导致代谢紊乱的主要因素。在还原应激条件下，α-硫辛酸通过将细胞内高NADH水平用作自身还原过程的辅助因子来降低其水平，而在氧化应激中，α-硫辛酸及其还原形式二氢硫辛酸可能通过直接清除自由基以及将其他抗氧化剂从其氧化形式中循环利用来发挥保护作用。
