Noto Hiroshi, Kawamura Mitsunobu, Hashimoto Yoshiaki, Satoh Hiroaki, Hara Masumi, Iso-o Naoyuki, Togo Masako, Kimura Satoshi, Tsukamoto Kazuhisa
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Atherosclerosis. 2003 Nov;171(1):131-6. doi: 10.1016/j.atherosclerosis.2003.08.005.
Probucol, an antioxidative and hypolipidemic agent, has been postulated to increase reverse cholesterol transport by enhancing cholesteryl ester transfer protein (CETP) activity. However, its clinical implication in CETP deficient patients has not been fully defined. To characterize the effects of probucol in the absence of CETP, we evaluated the changes in lipid profile, lipid peroxidation, and paraoxonase 1 (PON1) activity in two complete CETP deficient patients, caused by treatment with probucol. When the patients were not receiving probucol, low-density lipoprotein (LDL) particles were smaller and high-density lipoprotein (HDL) particles were larger in these patients than in controls. Treatment with probucol (500 mg/day) resulted in the decrease in the levels of HDL-C and apolipoprotein (apo) A-I up to 22%. The size of HDL particles became smaller. LDL cholesterol concentration did not change in one patient, while it decreased by 47% in the other. PON1 activity/HDL-C, which was about 40% lower in the patients before treatment than in controls with the matching PON1 genotype, increased by 30% during the treatment. Lag time for LDL and HDL in both cases became prolonged more than 1.8 times after administration of probucol. This study demonstrated for the first time that probucol reduces HDL-C even in humans with complete CETP deficiency. Probucol treatment in these patients was also associated with protection of lipoproteins against oxidative stress, suggesting a clinical benefit of this drug even in such a state.
普罗布考是一种抗氧化和降血脂药物，据推测它可通过增强胆固醇酯转运蛋白（CETP）活性来增加胆固醇逆向转运。然而，其在CETP缺乏患者中的临床意义尚未完全明确。为了明确在缺乏CETP的情况下普罗布考的作用，我们评估了两名完全缺乏CETP的患者在接受普罗布考治疗后血脂谱、脂质过氧化和对氧磷酶1（PON1）活性的变化。当患者未服用普罗布考时，与对照组相比，这些患者的低密度脂蛋白（LDL）颗粒较小，高密度脂蛋白（HDL）颗粒较大。服用普罗布考（500毫克/天）导致HDL-C和载脂蛋白（apo）A-I水平下降高达22%。HDL颗粒大小变小。一名患者的LDL胆固醇浓度未发生变化，而另一名患者的LDL胆固醇浓度下降了47%。治疗前患者的PON1活性/HDL-C比具有匹配PON1基因型的对照组低约40%，治疗期间增加了30%。在服用普罗布考后，两种情况下LDL和HDL的延迟时间延长超过1.8倍。这项研究首次证明，即使在完全缺乏CETP的人类中，普罗布考也会降低HDL-C。这些患者接受普罗布考治疗还与保护脂蛋白免受氧化应激有关，这表明即使在这种状态下，这种药物也具有临床益处。
