In Vitro Myotoxicity of the 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors, Pravastatin, Lovastatin, and Simvastatin, Using Neonatal Rat Skeletal Myocytes

Masters, Barbara A.; Palmoski, Marshall J.; Flint, Oliver; Gregg, Richard E.; Wang‐Iverson, David; Durham, Stephen K.

doi:10.1006/taap.1995.1058

Cited by 124 publications

(62 citation statements)

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“…They are more sensitive to statins than myoblasts. The toxic effects of hydrophilic pravastatin on the myotubes were observed at a mM range (13). Therefore, these cells were closer to the practical concentration (Table 1).…”

Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 58%

“…Therefore, these cells were closer to the practical concentration (Table 1). It was however difficult to observe statininduced morphological changes in myotubes because the statin treatment made myotubes shrink, unlike skeletal muscle fibers (13). In addition, it was difficult to examine the contractility of the myotubes, so they were not ideal for the analysis of statin myotoxicity.…”

Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 99%

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Mechanism of Statin-Induced Rhabdomyolysis

Sakamoto

Kimura

2013

J Pharmacol Sci

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Abstract. Statins, a group of drugs used for the treatment of hypercholesterolemia, have adverse effects on skeletal muscle. The symptoms of these effects range from slight myalgia to severe rhabdomyolysis. The number of patients currently taking statins is estimated to be several millions worldwide. However, the mechanism of statins' myotoxic effects is unclear. Statins inhibit biosynthesis of mevalonate, a rate-limiting step of cholesterol synthesis, by inhibiting HMG-CoA reductase. Mevalonate is also an essential precursor for producing isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. These isoprenoids are especially important for anchoring small GTPases to the membrane before they function; e.g., Ras GTPases modulate proliferation and apoptosis, Rho GTPases control cytoskeleton formation, and Rab GTPases are essential for intracellular vesicle trafficking. Inactivation of these small GTPases alters cellular functions. Recently, we successfully reproduced statin-induced myotoxicity in culture dishes using in vitro skeletal muscle systems (e.g., skeletal myotubes and myofibers). This review summarizes our findings that statins induce depletion of isoprenoids and inactivation of small GTPases, especially Rab, which are critical for statin-induced myotoxicity. Although further study is required, our findings may contribute to the prevention and treatment of statins' adverse effects on skeletal muscle and development of safer anti-hypercholesterolemia drugs.

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Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 58%

Section: In Vitro Skeletal Muscle Models For Statins Myotoxicitymentioning

confidence: 99%

Mechanism of Statin-Induced Rhabdomyolysis

Sakamoto

Kimura

2013

J Pharmacol Sci

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“…77 Moreover, we and others, have shown that the lactone ring is hydrolyzed to its active form when exposed to aqueous solution, including cell growth medium, strongly suggesting the pro-drug was activated in these in vitro studies. 60,78,79 Taken together, statins can growth arrest certain tumor sub-types by activating a well defined cell cycle checkpoint at the G1/S phase border by a mechanism that remains ill defined, but involves inhibition of HMG-CoA reductase.…”

Section: 71-73mentioning

confidence: 99%

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

et al. 2002

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The statin family of drugs target HMG-CoA reductase, the ratelimiting enzyme of the mevalonate pathway, and have been used successfully in the treatment of hypercholesterolemia for the past 15 years. Experimental evidence suggests this key biochemical pathway holds an important role in the carcinogenic process. Moreover, statin administration in vivo can provide an oncoprotective effect. Indeed, in vitro studies have shown the statins can trigger cells of certain tumor types, such as acute myelogenous leukemia, to undergo apoptosis in a sensitive and specific manner. Mechanistic studies show bcl-2 expression is down-regulated in transformed cells undergoing apoptosis in response to statin exposure. In addition, the apoptotic response is in part due to the depletion of the downstream product geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate or other products of the mevalonate pathway including cholesterol. Clinically, preliminary phase I clinical trials have shown the achievable plasma concentration corresponds to the dose range that can trigger apoptosis of tumor types in vitro. Moreover, little toxicity was evident in vivo even at high concentrations. Clearly, additional clinical trials are warranted to further assess the safety and efficacy of statins as novel and immediately available anti-cancer agents. In this article, the experimental evidence supporting a role for the statin family of drugs to this new application will be reviewed.

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“…In vitro and in vivo data support this supposition, demonstrating that lower exposures are observed for pravastatin than for lovastatin and simvastatin in the central nervous system, 142,143 and pravastatin also manifests a lower risk of myopathy than simvastatin and atorvastatin do. [144][145][146][147][148][149] However, there are contradictory data which suggest that pravastatin can influence gene expression in the central nervous system to the same extent as some of the other statins. 143 Until the active transporters responsible for tissue distribution of the statins and their ontogeny in children are more fully elucidated, practitioners will need to rely on the adverse event profiles reported from clinical studies.…”

Section: Distributionmentioning

confidence: 99%

Pediatric Statin Administration: Navigating a Frontier with Limited Data

Wagner

Abdel‐Rahman

2016

The Journal of Pediatric Pharmacology and Therapeutics

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Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs.

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In Vitro Myotoxicity of the 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitors, Pravastatin, Lovastatin, and Simvastatin, Using Neonatal Rat Skeletal Myocytes

Cited by 124 publications

References 0 publications

Mechanism of Statin-Induced Rhabdomyolysis

Mechanism of Statin-Induced Rhabdomyolysis

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

Pediatric Statin Administration: Navigating a Frontier with Limited Data

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