Inhibition of Cholesterol Synthesis by Squalene Synthase Inhibitors Does Not Induce Myotoxicityin Vitro

Flint, Oliver; Masters, Barbara A.; Gregg, Richard E.; Durham, Stephen K.

doi:10.1006/taap.1997.8131

Cited by 127 publications

(68 citation statements)

References 36 publications

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“…9 ), consistent with previous reports of its lack of toxicity ( 26 ). Inhibition of protein synthesis has previously been reported to be a measure of the cytotoxic effects of chemical agents [e.g., ( 41,42 )] and, in some cases, has been found to be at least as sensitive as or more sensitive than the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay ( 43 ). Thus, our data indicate that the activation of PLD in response to cell wounding probably plays a key role in allowing the cell to repair plasma membrane disruptions.…”

Section: Effect Of Provision Of Pg On Wound Healing In Vivosupporting

confidence: 87%

Cell wounding activates phospholipase D in primary mouse keratinocytes

Arun

Xie

Howard

et al. 2013

Journal of Lipid Research

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Journal of Lipid Research Volume 54, 2013 581characterized by growth arrest and expression of the mature keratins 1 and 10 in the fi rst differentiated layer of the epidermis, the spinous layer. Early differentiation in the spinous layer is followed by further differentiation in the granular layer, which is accompanied by expression of proteins that are essential for the formation of the cornifi ed envelope and corneocytes. The corneocytes constitute the outer layer of the epidermis, the stratum corneum, and give skin its resilience to mechanical stress (as reviewed in Ref. 1 ). Defi ciencies in the mechanical barrier function of the epidermis result in skin diseases. For example, epidermolysis bullosa simplex and epidermolytic hyperkeratosis arise through mutations in keratins comprising the intermediate fi laments and are characterized by extensive blistering and epidermal sloughing as a result of the mechanical stresses encountered by routine interactions with the environment (as reviewed in Ref.2 ). Many tissues of the body in addition to the skin are exposed to mechanical stresses that result in tearing, or disrupting, the plasma membrane of the constituent cells. These disruptions will result in cell death if left unrepaired. However, cells possess an active plasma membrane repair process that can restore plasma membrane integrity if the disruption is not too extensive (as reviewed in Ref.3 ). For example, intestinal cells in the gastrointestinal tract are subjected to mechanical perturbations during the transit of a food bolus; these plasma membrane disruptions can be repaired to allow cell survival ( 4-6 ). Similarly, eccentric contraction of skeletal muscle as a result of downhill treadmill running induces plasma membrane disruptions that are largely repaired ( 7 ). Routine ambulation also appears to lead to plasma membrane disruptions in the epidermis of the digits ( 8 ). Therefore, it is critical that cells in these mechanically active tissues be able to repair membrane Keratinocytes form the epithelium of the skin, the epidermis, and comprise several cell layers. As keratinocytes migrate up from the stratum basale, they undergo a distinct pattern of differentiation that is essential for the function of the skin as a protective barrier. This pattern is Abbreviations: 1,25(OH) 2 D 3 , 1,25-dihydroxyvitamin D 3 ; AQP3, aquaporin 3; FIPI, 5-fl uoro-2-indolyl des-chlorohalopemide; HBSS, Hank's buffered salt solution; K-SFM, keratinocyte serum-free medium; PEt, phosphatidylethanol; PG, phosphatidylglycerol; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PLD, phospholipase D; SFKM, serum-free keratinocyte medium; TPA, 12-O -tetradecanoylphorbol 13-acetate.

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Section: Effect Of Provision Of Pg On Wound Healing In Vivosupporting

confidence: 87%

Cell wounding activates phospholipase D in primary mouse keratinocytes

Arun

Xie

Howard

et al. 2013

Journal of Lipid Research

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“…Thus, statin-induced depletion of these isoprenoids invites inactivation of small GTPases. Durham et al revealed that lovastatin reduced prenylation of small GTPases and that supplementation of the geranylgeranyl group (geranylgeraniol: 1 -30 mM) or farnesyl group (farnesol: 1 -100 mM) canceled the lovastatin-induced loss of ATP in rat primary cultured myotubes (21). However, it is unclear in their study which isoprenoid depletion is more important for statin-induced myotoxicity.…”

Section: Depletion Of Geranylgeranylpyrophosphate Triggers Statin Myomentioning

confidence: 99%

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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“…Blocking cholesterol synthesis with squalene synthase inhibitors does not produce myotoxicity in vitro models (Fig. 1), suggesting that cholesterol synthesis changed by statins is not responsible, and that some other compounds are (17). CoQ10 is a substance found within mitochondrial enzymes, and aids them by supplying energy for the function of cells with particularly high metabolic demands, such as those within the heart muscle, liver and pancreas.…”

Section: Mevalonate Pathway and Coq10mentioning

confidence: 99%

“…In It is hoped that the development of a new generation of cholesterol-reducing drugs will affect the biosynthesis of cholesterol below the farnesyl pyorophosphate branch point of the mevalonate pathway and thus will not inhibit CoQ10 biosynthesis (17).…”

Section: Supplementation Of Coq10 To Prevent Adverse Effects Of Statinsmentioning

confidence: 99%

Reduction of Serum Ubiquinol-10 and Ubiquinone-10 Levels by Atorvastatin in Hypercholesterolemic Patients

Mabuchi

Higashikata

Kawashiri

et al. 2005

JAT

107

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Reduction of serum cholesterol levels with statin therapy decreases the risk of coronary heart disease. Inhibition of HMG-CoA reductase by statin results in decreased synthesis of cholesterol and other products downstream of mevalonate, which may produce adverse effects in statin therapy. We studied the reductions of serum ubiquinol-10 and ubiquinone-10 levels in hypercholesterolemic patients treated with atorvastatin. Fourteen patients were treated with 10 mg/day of atorvastatin, and serum lipid, ubiquinol-10 and ubiquinone-10 levels were measured before and after 8 weeks of treatment. Serum total cholesterol and LDL-cholesterol levels decreased significantly. All patients showed definite reductions of serum ubiquinol-10 and ubiquinone-10 levels, and mean levels of serum ubiquinol-10 and ubiquinone-10 levels decreased significantly from 0.81 ± ± ± ± ± 0.21 to 0.46 ± ± ± ± ± 0.10 µ µ µ µ µg/ml (p < 0.0001), and from 0.10 ± ± ± ± ± 0.06 to 0.06 ± ± ± ± ± 0.02 µ µ µ µ µg/ml (p = 0.0008), respectively. Percent reductions of ubiquinol-10 and those of total cholesterol showed a positive correlation (r = 0.627, p = 0.0165). As atorvastatin reduces serum ubiquinol-10 as well as serum cholesterol levels in all patients, it is imperative that physicians are forewarned about the risks associated with ubiquinol-10 depletion. J Atheroscler Thromb, 2005; 12: 111-119.

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Inhibition of Cholesterol Synthesis by Squalene Synthase Inhibitors Does Not Induce Myotoxicityin Vitro

Cited by 127 publications

References 36 publications

Cell wounding activates phospholipase D in primary mouse keratinocytes

Cell wounding activates phospholipase D in primary mouse keratinocytes

Mechanism of Statin-Induced Rhabdomyolysis

Reduction of Serum Ubiquinol-10 and Ubiquinone-10 Levels by Atorvastatin in Hypercholesterolemic Patients

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