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Keywords:

  • free radicals;
  • Trolox;
  • alpha-tocopherol;
  • WIN 62079;
  • U-78517F

Abstract

Alpha-tocopherol and its water-soluble derivative, Trolox, are capable of terminating free radical chain reactions and limiting reperfusion-induced cell damage. In the present study, we have quantitated the effects of two relatively potent analogs of alpha-tocopherol/Trolox, WIN 62079 and U-78517F, which attenuated exogenously generated free radical damage in cultured cells and reperfusion injury in vivo. In a cultured rat renal tubular epithelial cell line (NRK-52E), millimolar concentrations of ascorbate or the combination of Trolox plus ascorbate reduced cellular damage (quantitated as lactate dehydrogenase [LDH] release) induced by radicals generated by hypoxanthine/xanthine oxidase. In contrast, WIN 62079 and U-78517F attenuated damage at micromolar concentrations. Similarly, intravenous administration of WIN 62079 (three hourly doses of 3 mg/kg) and U-78517F (10 mg/kg infused over 5 min) reduced reperfusion-induced myocardial damage in rabbit coronary-occulded hearts: Trolox (three hourly doses of 100 mg/kg) was less potent and required ascorbate (three hourly doses of 150 mg/kg) as a cofactor. These data demonstrate that is feasible to design potent, water-soluble analogs of Trolox which are efficacious against free radical-mediated cell death and which do not require ascorbate as a cofactor. Moreover, since U-78517F and WIN 62079 are two to three orders of magnitude more potent than Trolox, and since they contain different amino side chains, these data further support the concept that side chain modifications of the chromane ring nucleus of alpha-tocopherol derivatives significantly affect activity, possibly by providing additional activity or by enhancing availability to the cellular site of action. © 1992 Wiley-Liss, Inc.