Abstract
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 α (PPARα) agonist. Consistent with these data, a marked expression for PPARα 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 PPARα. Moreover, our present cell injury model using HRMSC may be useful for elucidating the mechanisms of clinical rhabdomyolysis induced by lipid-lowering agents.
Similar content being viewed by others
References
Brown P, Winegar D, Plunket K, Moore L, Lewis M, Wilson J, Sundseth S, Koble C, Wu Z, Chapman J, Lehmann J, Kliewer S, Willson T (1999) A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARalpha agonist with potent lipid-lowering activity. J Med Chem 42:3785–3788
Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najb J, Staels B (1998) Activation of proliferator-activated receptors α and δ induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273:255573–255580
Coxon FP, Benford HL, Russell RG, Rogers MJ (1998) Protein synthesis is required for caspase activation and induction of apoptosis by bisphosphonate drugs. Mol Pharmacol 54:631–638
Diep QN, Touyz RM, Schiffrin EL (2000) Docosahexaenoic acid, a peroxisome proliferator-activated receptor-alpha ligand, induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase. Hypertension 36:851–855
Dimitroulakos J, Nohynek D, Backway KL, Hedley DW, Yeger H, Freedman MH, Minden MD, Penn LZ (1999) Increased sensitivity of acute myelogenous leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 93:1308–1318
Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M (2001) Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins). Br J Pharmacol 133:1172–1180
Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc Natl Acad Sci USA 94:4312–4317
Goa KL, Barradell LB, Plosker GL (1996) Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia. Drugs 52:725–753
Gonzalez FJ, Peters JM, Cattley RC (1998) Mechanism of action of the nongenotoxic peroxisome proliferator-activator receptor alpha. J Natl Cancer Inst 90:1702–1709
Gotto AM Jr (1998) Triglyceride as a risk factor for coronary artery disease. Am J Cardiol 82:22Q–25Q
Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J (1998) 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 83:490–500
Guyton JR (1999) Combination drug therapy for combined hyperlipidemia. Curr Cardiol Rep 1:244–250
Holden PR, Tugwood JD (1999) Peroxisome proliferation-activated receptor α: role in rodent liver cancer and species differences. J Mol Endocrinol 22:1–8
Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S (2002) Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFκB. Biochem Biophys Res Commun 290:131–139
Lau TK, Leachman DR, Lufschanowski R (2001) Severe rhabdomyolysis associated with the cerivastin-gemfibrozil combination therapy: report of a case. Tex Heart Inst J 28:142–145
Maddala RL, Reddy VN, Rao PV (2001) Lovastatin-induced cytoskeletal reorganization in lens epithelial cells: role of Rho GTPases. Invest Ophthalmol Vis Sci 42:2610–2615
Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B (2001) Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest 107:1423–1432
Moghadasian MH (1999) Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci 65:1329–1337
Moghadasian MH, Mancini GB, Frohlich JJ (2000) Pharmacotherapy of hypercholesterolaemia: statins in clinical practice. Expert Opin Pharmacother 1:683–695
Muga SJ, Thuillier P, Pavone A, Rundhaug JE, Boeglin WE, Jisaka M, Brash AR, Fischer SM (2000) 8S-lipoxygenase products activate peroxisome proliferator-activated receptor alpha and induce differentiation in murine keratinocytes. Cell Growth Differ 11:447–454
Omar MA, Wilson JP, Cox TS (2001) Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 35:1096–1107
Padayatty SJ, Marcelli M, Shao TC, Cunningham GR (1997) Lovastatin-induced apoptosis in prostate stromal cells. J Clin Endocrinol Metab 82:1434–1439
Pastorino JG, Chen ST, Tafani M, Snyder JW, Farber JL (1998) The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition. J Biol Chem 273:7770–7775
Pastorino JG, Tafani M, Rothman RJ, Marcinkeviciute A, Hoek JB, Farber JL, Marcineviciute A (1999) Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore. J Biol Chem 274:31734–31739
Perez-Sala D, Mollinedo F (1993) Inhibition of isoprenoid biosynthesis induces apoptosis in human promyelocytic HL-60 cells. Biochem Biophys Res Commun 199:1209–1215
Poels PJ, Gabreels FJ (1993) Rhabdomyolysis: a review of the literature. Clin Neurol Neurosurg 95:175–192
Robins SJ (2001) PPARalpha ligands and clinical trials: cardiovascular risk reduction with fibrates. J Cardiovasc Risk 8:195–201
Sgro C, Escousse A (1991) Side effects of fibrates (except liver and muscle). Therapie 46:351–354
Sharobeem KM, Madden BP, Millner R, Rolfe LM, Seymour CA, Parker J (2000) Acute renal failure after cardiopulmonary bypass: a possible association with drugs of the fibrate group. J Cardiovasc Pharmacol Ther 5:33–39
Shek A, Ferrill MJ (2001) Statin-fibrate combination therapy. Ann Pharmacother 35:908–917
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart J-C (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98:2088–2093
Tanaka T, Tatsuno I, Uchida D, Moroo I, Morio H, Nakamura S, Noguchi Y, Yasuda T, Kitagawa M, Saito Y, Hirai A (2000) Geranylgeranyl-pyrophosphate, an isoprenoid of mevalonate cascade, is a critical compound for rat primary cultured cortical neurons to protect the cell death induced by 3-hydroxy-3-methylglutaryl-CoA reductase inhibition. J Neurosci 20:2852–2859
Veerkamp JH, Smit JW, Benders AA, Oosterhof A (1996) Effects of HMG-CoA reductase inhibitors on growth and differentiation of cultured rat skeletal muscle cells. Biochim Biophys Acta 1315:217–222
Winegar DA, Brown PJ, Wilkison WO, Lewis MC, Ott RJ, Tong WQ, Brown HR, Lehmann JM, Kliewer SA, Plunket KD, Way JM, Bodkin NL, Hansen BC (2001) Effects of fenofibrate on lipid parameters in obese rhesus monkeys. J Lipid Res 42:1543–1551
Yu K, Bayona W, Kallen CB, Harding HP, Ravera CP, McMahon G, Brown M, Lazar MA (1995) Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem 270:23975–23983
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Maiguma, T., Fujisaki, K., Itoh, Y. et al. Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells. Naunyn-Schmiedeberg's Arch Pharmacol 367, 289–296 (2003). https://doi.org/10.1007/s00210-002-0660-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-002-0660-9