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Statins and PPARα agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment
Johnson T.E.; Zhang X.; Shi S.; Umbenhauer D.R.
2005-11-01
Source PublicationToxicology and Applied Pharmacology
ISSN0041008X 10960333
Volume208Issue:3Pages:210-221
AbstractStatins and fibrates (weak PPARα agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPARα agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPARα compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPARγ agonist Rosiglitazone caused little or no cell death at up to 10 μM and the PPARδ ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPARα agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPARα agonism mediates in part the toxicity response to PPARα compounds. Furthermore, PPARα agonists and statins cause myotoxicity through distinct and independent pathways. © 2005 Elsevier Inc. All rights reserved.
KeywordCo-treatment Myopathy Myotoxicity Statin PPAR Synergy
DOI10.1016/j.taap.2005.03.004
URLView the original
Language英語
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Cited Times [WOS]:31   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
AffiliationMerck Research Laboratories
Recommended Citation
GB/T 7714
Johnson T.E.,Zhang X.,Shi S.,et al. Statins and PPARα agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment[J]. Toxicology and Applied Pharmacology,2005,208(3):210-221.
APA Johnson T.E.,Zhang X.,Shi S.,&Umbenhauer D.R..(2005).Statins and PPARα agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment.Toxicology and Applied Pharmacology,208(3),210-221.
MLA Johnson T.E.,et al."Statins and PPARα agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment".Toxicology and Applied Pharmacology 208.3(2005):210-221.
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