O'Brien R C, Luo M
Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Metabolism. 1997 Dec;46(12 Suppl 1):22-5. doi: 10.1016/s0026-0495(97)90312-7.
Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.
糖尿病与氧化应激增加有关。这可能通过低密度脂蛋白（LDL）氧化增加促进糖尿病大血管并发症的发生，而LDL氧化被认为是动脉粥样硬化发展的关键步骤。磺脲类药物格列齐特在体外已显示出自由基清除活性，但其对LDL氧化的影响以及其他磺脲类药物的此类作用尚不清楚。为了研究这一点，我们研究了用1μmol/L格列齐特体外补充对从20名对照受试者和22名II型糖尿病患者分离的LDL铜诱导氧化的影响。同时研究了1μmol/L维生素C（一种已知的水溶性抗氧化剂）的作用。用格列齐特和维生素C处理后，氧化抗性（以添加铜和开始氧化之间的延迟时间表示）均显著增加，糖尿病受试者和对照受试者的LDL的作用相似。基线氧化延迟时间为63.4±2.1分钟，用格列齐特后增加到108±4.4分钟，用维生素C后增加到88.7±5.6分钟（P = 0.0001，基线与任一处理组相比）。格列齐特使延迟时间增加70%±3%，大于维生素C使延迟时间增加30%±5%（P < 0.0005）。在另一项实验中，从8名对照受试者和10名糖尿病受试者分离的LDL分别用1μmol/L格列齐特、格列本脲、格列吡嗪和甲苯磺丁脲进行补充。对于每个LDL样本，所有药物同时进行研究，并将氧化延迟时间与未处理的LDL进行比较。格列齐特使延迟时间从53.7±2.4分钟增加到108.4±4.5分钟（P = 0.0001）。其他磺脲类药物对延迟时间均无影响。这些发现表明，格列齐特是体外LDL氧化的有效抑制剂，在这方面，按摩尔计算它比维生素C更有效。格列齐特的这种抗氧化特性未被所研究的其他磺脲类药物共享。
