Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells.
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.
Maiguma
Takayoshi
T
Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 812-8582 Fukuoka, Japan.
Fujisaki
Koji
K
Itoh
Yoshinori
Y
Makino
Kazutaka
K
Teshima
Daisuke
D
Takahashi-Yanaga
Fumi
F
Sasaguri
Toshiyuki
T
Oishi
Ryozo
R
D001629:Bezafibrate / Q000009:adverse effects; D002994:Clofibrate / Q000009:adverse effects; D002995:Clofibric Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004357:Drug Synergism; D011345:Fenofibrate / Q000009:adverse effects; D058607:Fibric Acids; D015248:Gemfibrozil / Q000009:adverse effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018233:Rhabdomyosarcoma, Embryonal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D019821:Simvastatin / Q000009:adverse effects; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002995:Clofibric Acid; D019821:Simvastatin; C019304:ciprofibrate; D002994:Clofibrate; D015248:Gemfibrozil; D011345:Fenofibrate; D001629:Bezafibrate