Maiguma Takayoshi, Fujisaki Koji, Itoh Yoshinori, Makino Kazutaka, Teshima Daisuke, Takahashi-Yanaga Fumi, Sasaguri Toshiyuki, Oishi Ryozo
Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 812-8582 Fukuoka, Japan.
Naunyn Schmiedebergs Arch Pharmacol. 2003 Mar;367(3):289-96. doi: 10.1007/s00210-002-0660-9. Epub 2003 Feb 8.
The effects of a variety of fibrates on the cell viability were examined in human embryonal rhabdomyosarcoma cells (HRMSC). Five fibrates, including fenofibrate, clofibrate, gemfibrozil, bezafibrate and ciprofibrate, all concentration-dependently reduced the cell viability determined by the mitochondrial enzyme activity. The cell injury occurred time-dependently and was marked at 24-48 h. The toxic action of fibrates was specific to HRMSC, since bezafibrate did not induce any marked changes in the viability of human microvascular endothelial cells or arterial smooth muscle cells. Synergistic cell injury was observed after a combined treatment with bezafibrate and simvastatin, although simvastatin alone reduced the cell viability. The cell injury was characterized by a typical nuclear damage, as evidenced by Hoechst 33342 staining and deoxynucleotidyl transferase dUTP nick-end label-positive staining. Similar cell-specific injury was induced by 8(S)-hydroxyeicosatetraenoic acid, a potent peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. Consistent with these data, a marked expression for PPARalpha mRNA was observed in HRMSC but not in the endothelial or smooth muscle cells. Therefore, it is suggested that fibrates cause a cell-specific injury in HRMSC via activation of PPARalpha. Moreover, our present cell injury model using HRMSC may be useful for elucidating the mechanisms of clinical rhabdomyolysis induced by lipid-lowering agents.
在人胚胎性横纹肌肉瘤细胞（HRMSC）中检测了多种贝特类药物对细胞活力的影响。五种贝特类药物，包括非诺贝特、氯贝丁酯、吉非贝齐、苯扎贝特和环丙贝特，均呈浓度依赖性地降低了通过线粒体酶活性测定的细胞活力。细胞损伤呈时间依赖性发生，在24 - 48小时时最为明显。贝特类药物的毒性作用对HRMSC具有特异性，因为苯扎贝特并未诱导人微血管内皮细胞或动脉平滑肌细胞的活力发生任何显著变化。苯扎贝特与辛伐他汀联合治疗后观察到协同性细胞损伤，尽管单独使用辛伐他汀也降低了细胞活力。细胞损伤的特征是典型的核损伤，Hoechst 33342染色和脱氧核苷酸末端转移酶介导的dUTP缺口末端标记阳性染色证明了这一点。8(S)-羟基二十碳四烯酸（一种有效的过氧化物酶体增殖物激活受体α（PPARα）激动剂）也诱导了类似的细胞特异性损伤。与这些数据一致，在HRMSC中观察到PPARα mRNA有明显表达，但在内皮细胞或平滑肌细胞中未观察到。因此，提示贝特类药物通过激活PPARα在HRMSC中引起细胞特异性损伤。此外，我们目前使用HRMSC的细胞损伤模型可能有助于阐明降脂药物诱导临床横纹肌溶解的机制。
