Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in     Watanabe heritable hyperlipidemic rabbits

    抗动脉粥样硬化和降脂药物普罗布考(0.5-1%)或天然抗氧化剂槲皮素(1%)，胆固醇饲养（1.5%）小鼠给药六周，WHHL家兔给药8周研究血浆和脂蛋白的氧化情况。利用MDA-HPLC法测定丙二醛总量(nmol MDA/g 蛋白)分析氧化程度。与对照组相比，普罗布考显著升高WHHL家兔和胆固醇饲养小鼠LDL中MDA含量 (WHHL家兔：1778.7+/-585.5 nmol/g vs. 394.4+/-144.5 nmol/g, P < 0.001；胆固醇饲养小鼠579.7 + 47.3 nmol/g vs. 408.1+/-85.8 nmol/g, P < 0.05)，而LDL胆固醇有所降低（WHHL家兔: P < 0.05; 小鼠: P < 0.01）。同时对WHHL家兔氧化VLDL 进行测定，普罗布考治疗组同样有较大增加(2102.7+/-1156.1 nmol/g vs. 455.0+/-207.8 nmol/g, P< 0.01)。与此相反，普罗布考治疗动物血浆和HDL氧化未显示统计学意义上的增加，提示普罗布考调节导致动脉粥样硬化的胆固醇转运蛋白选择性氧化。槲皮素治疗组LDL（家兔组VLDL） 的氧化未发生增加，胆固醇水平未有所降低。此外未发现槲皮素的抗氧化保护作用。总之，结果显示在动物模型中，氧化强化机制比抗氧化作用对脂蛋白代谢影响更大。推测脂蛋白氧化可能是由巨噬细胞或其他细胞（通过巨噬细胞和肝脏）吸收或降解过量LDL或VLDL引起的生理机制。普罗布考氧化导致动脉粥样硬化的脂蛋白从而降低胆固醇的水平。


    The anti-atherogenic and cholesterol-lowering drug probucol (0.5-1%) or quercetin (1%), a natural antioxidant, was   given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes in plasma and lipoproteins.Oxidation was measured as the total  amount of malondialdehyde (nmol MDA/g protein) by a very specific   MDA-HPLC method. A large and significant increase in MDA was seen in LDL from probucol treated WHHL rabbits (1778.7+/-585.5 nmol/g vs. 394.4+/-144.5 nmol/g, P < 0.001) and   cholesterol-fed mice (579.7 + 47.3 nmol/g vs.408.1+/-85.8 nmol/g, P < 0.05) as compared to controls while LDL cholesterol was lowered (WHHL rabbits: P < 0.05; mice: P < 0.01). In WHHL rabbits VLDL oxidation was determined additionally,and also revealed a large increase in the probucol group (2102.7+/-1156.1 nmol/g vs. 455.0+/-207.8 nmol/g, P< 0.01). In contrast, the oxidation of plasma and HDL from probucol treated animals was not statistically significantly increased,implying that probucol mediates a selective oxidation of atherogenic cholesterol-transporting lipoproteins. Quercetin treated animals  did not show increased oxidation of LDL (and VLDL in rabbits) and cholesterol levels were not decreased. Furthermore, no protective antioxidant effect of quercetin was seen.In conclusion, the results suggest that a prooxidant mechanism rather than antioxidative effects influences  lipoprotein metabolism in these animals. It is hypothesized that the oxidation of lipoproteins might be a physiological   mechanism performed by macrophages or other cells for uptake and degradation (by macrophages and liver) of excessive amounts of LDL or VLDL and that probucol oxidizes atherogenic lipoproteins and       thereby leads to a decrease in cholesterol levels.