Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and in combination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.
- MeSH
- C-reaktivní protein genetika MeSH
- fenofibrát toxicita MeSH
- glukosa metabolismus MeSH
- hypolipidemika toxicita MeSH
- jaterní testy MeSH
- krysa rodu rattus MeSH
- lékové postižení jater genetika patologie MeSH
- lidé MeSH
- metabolický syndrom metabolismus MeSH
- potkani inbrední SHR MeSH
- potkani transgenní MeSH
- rosuvastatin kalcium farmakologie MeSH
- statiny farmakologie MeSH
- stearyl-CoA-desaturasa genetika metabolismus MeSH
- tuková tkáň účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Clofibric acid (CA) is the active substance of lipid lowering drugs. It is resistant to degradation, polar in nature, and has been found ubiquitously in the aquatic environment. Though CA is classified as a peroxisomal proliferator in rodents and is considered as a potential endocrine disruptor, little information exists on the effects of CA in aquatic organisms, such as fish. In the present study, we examined the mRNA levels of peroxisome proliferator- and estrogen-sensitive genes on the exposure of primary rainbow trout (Oncorhynchus mykiss) hepatocytes to CA alone and in combination with the natural female sex hormone, 17β-estradiol (E2). Our results demonstrate that rainbow trout hepatocytes are relatively refractory to the effects of CA on the PPAR signaling pathway and lipid metabolism. Moreover, CA did not show recognizable estrogenic activity, but after the induction of vitellogenesis by E2, CA significantly reduced vitellogenin (VTG) mRNA abundance. Apparently, the indirect repression of VTG transcription, independent of estrogen receptors, occurred. The mechanism is not yet clearly understood but may involve disruption of the stabilization of VTG mRNA known to be induced by E2.
- MeSH
- apolipoprotein C-II genetika MeSH
- chemické látky znečišťující vodu toxicita MeSH
- cytochrom P-450 CYP3A genetika MeSH
- estradiol toxicita MeSH
- glutathiontransferasa genetika MeSH
- hepatocyty účinky léků metabolismus MeSH
- hypolipidemika toxicita MeSH
- kultivované buňky MeSH
- kyselina klofibrová toxicita MeSH
- messenger RNA metabolismus MeSH
- modulátory estrogenních receptorů toxicita MeSH
- Oncorhynchus mykiss * MeSH
- rybí proteiny genetika MeSH
- systém (enzymů) cytochromů P-450 genetika MeSH
- vitelogeniny genetika MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Purpose of review: Lipid-lowering drugs are associated with myotoxicity, which ranges in severity from myalgias to rhabdomyolysis resulting in renal failure and death. Although rhabdomyolysis is rare, muscle symptoms and serum creatine kinase elevations are sufficiently frequent during the course of lipid-lowering drug therapy to pose diagnostic challenges for the clinician. Progress in our understanding of this form of myotoxicity is reviewed. Recent findings: Muscle pain and weakness are the cardinal symptoms and often interfere with vigorous exercise. These symptoms may occur with or without serum creatine kinase elevations. The risk of myotoxicity is increased by combination statin-fibrate therapy as well as by factors that elevate tissue levels of the lipid-lowering drug, including the dose, drug-drug interactions, and host factors. Underlying neuromuscular diseases may become clinically apparent during statin therapy and may predispose to myotoxicity. The pathophysiology of myotoxicity most probably involves metabolic effects of the statins on the isoprenoid pool and on mitochondrial function. Summary: Management of myotoxicity requires an evaluation of risk factors prior to prescribing lipid-lowering drugs, attention to muscle symptoms, and withdrawal of drug in the event of significant abnormalities.
- MeSH
- hypolipidemika škodlivé účinky toxicita MeSH
- lidé MeSH
- myozitida farmakoterapie imunologie komplikace MeSH
- nemoci svalů farmakoterapie prevence a kontrola terapie MeSH
- nežádoucí účinky léčiv komplikace MeSH
- plošný screening metody využití MeSH
- rhabdomyolýza farmakoterapie imunologie komplikace MeSH
- rizikové faktory MeSH
- statiny škodlivé účinky toxicita MeSH
- Check Tag
- lidé MeSH
- MeSH
- hypolipidemika toxicita MeSH
- myši MeSH
- plod účinky léků MeSH
- těhotenství MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
