Paterna J C, Boess F, Stäubli A, Boelsterli U A
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach, Switzerland.
Toxicol Appl Pharmacol. 1998 Jan;148(1):117-25. doi: 10.1006/taap.1997.8315.
D-Tagatose is a zero-energy producing ketohexose that is a powerful cytoprotective agent against chemically induced cell injury. To further explore the underlying mechanisms of cytoprotection, we investigated the effects of D-tagatose on both the generation of superoxide anion radicals and the consequences of oxidative stress driven by prooxidant compounds in intact cells. Primary cultures of hepatocytes derived from male C57BL/6 mice were exposed to the redox cycling drug nitrofurantoin (NFT). Lethal cell injury induced by 300 microM NFT was completely prevented by high concentrations (20 mM) of D-tagatose, whereas equimolar concentrations of glucose, mannitol, or xylose were ineffective. The extent of NFT-induced intracellular superoxide anion radical formation was not altered by D-tagatose, indicating that the ketohexose did not inhibit the reductive bioactivation of NFT. However, the NFT-induced decline of the intracellular GSH content was largely prevented by D-tagatose. The sugar also afforded complete protection against NFT toxicity in hepatocytes that had been chemically depleted of GSH. Furthermore, the ketohexose fully protected from increases in both membrane lipid peroxidation and protein carbonyl formation. In addition, D-tagatose completely prevented oxidative cell injury inflicted by toxic iron overload with ferric nitrilotriacetate (100 microM). In contrast, D-tagatose did not protect against lethal cell injury induced by tert-butyl hydroperoxide, a prooxidant which acts by hydroxyl radical-independent mechanisms and which is partitioned in the lipid bilayer. These results indicate that D-tagatose, which is a weak iron chelator, can antagonize the iron-dependent toxic consequences of intracellular oxidative stress in hepatocytes. The antioxidant properties of D-tagatose may result from sequestering the redox-active iron, thereby protecting more critical targets from the damaging potential of hydroxyl radical.
D-塔格糖是一种不产生能量的酮己糖，是一种强大的细胞保护剂，可抵御化学诱导的细胞损伤。为了进一步探究细胞保护的潜在机制，我们研究了D-塔格糖对完整细胞中超氧阴离子自由基生成以及由促氧化剂化合物驱动的氧化应激后果的影响。将源自雄性C57BL/6小鼠的原代肝细胞培养物暴露于氧化还原循环药物呋喃妥因（NFT）。高浓度（20 mM）的D-塔格糖可完全预防300 microM NFT诱导的致死性细胞损伤，而等摩尔浓度的葡萄糖、甘露醇或木糖则无效。D-塔格糖不会改变NFT诱导的细胞内超氧阴离子自由基形成的程度，这表明该酮己糖不会抑制NFT的还原性生物活化。然而，D-塔格糖在很大程度上预防了NFT诱导的细胞内谷胱甘肽（GSH）含量下降。该糖还为已被化学耗尽GSH的肝细胞提供了完全的NFT毒性防护。此外，该酮己糖完全防止了膜脂质过氧化和蛋白质羰基形成的增加。此外，D-塔格糖完全预防了由次氮基三乙酸铁（100 microM）引起的有毒铁过载所导致的氧化性细胞损伤。相比之下，D-塔格糖不能预防叔丁基过氧化氢诱导的致死性细胞损伤，叔丁基过氧化氢是一种通过不依赖羟基自由基的机制起作用且分布于脂质双层中的促氧化剂。这些结果表明，作为一种弱铁螯合剂的D-塔格糖可以拮抗肝细胞内氧化应激的铁依赖性毒性后果。D-塔格糖的抗氧化特性可能源于螯合具有氧化还原活性的铁，从而保护更关键的靶点免受羟基自由基的破坏潜力。
