Statin Toxicity Research Articles

Geranylgeraniol prevents the cytotoxic effects of mevastatin in THP‐1 cells, without decreasing the beneficial effects on cholesterol synthesis

Statins, inhibitors of hydroxymethylglutaryl-CoA reductase, reduce the intracellular synthesis of cholesterol and prevent the onset of atherosclerosis. They also decrease the synthesis of isoprenoid molecules, such as the side chain of ubiquinone and geranylgeranyl pyrophosphate. As a consequence, statins impair mitochondrial metabolism and the activation of small monomeric GTPases (such as Rho and Ras), causing toxic effects. To date, a successful strategy to prevent statin toxicity is lacking. In human monocytic THP-1 cells, we measured the synthesis of cholesterol and isoprenoids, mitochondrial electron flow, the activity of RhoA and Rac, cell death and proliferation. Mevastatin reduced the synthesis of cholesterol, geranylgeranyl pyrophosphate and ubiquinone, mitochondrial electron transport, activity of RhoA and Rac, and cell proliferation, accompanied by increased cell death. Geranylgeraniol, a cell-permeable analogue of geranylgeranyl pyrophosphate, reversed all these effects of mevastatin, without affecting its ability to reduce cholesterol synthesis. Notably, geranylgeraniol was more effective than the addition of exogenous ubiquinone, which rescued mitochondrial respiratory activity and reversed mevastatin cytotoxicity, but did not alter the decrease in cell proliferation. The same results were obtained in human liver HepG2 cells. Geranylgeraniol had a broader protective effect against the cytotoxicity of statins than exogenous ubiquinone. Therefore, geranylgeraniol may be a more useful and practical means of limiting the toxicities of statins, without reducing their efficacy as cholesterol lowering agents.

Human Skeletal Muscle Drug Transporters Determine Local Exposure and Toxicity of Statins

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, are important drugs used in the treatment and prevention of cardiovascular disease. Although statins are well tolerated, many patients develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare but severe toxicity of statins. Interindividual differences in the activities of hepatic membrane drug transporters and metabolic enzymes are known to influence statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is known regarding the molecular determinants of statin distribution into skeletal muscle and its relevance to toxicity. We sought to identify statin transporters in human skeletal muscle and determine their impact on statin toxicity in vitro. We demonstrate that the uptake transporter OATP2B1 (human organic anion transporting polypeptide 2B1) and the efflux transporters, multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin and rosuvastatin are substrates of these transporters when assessed using a heterologous expression system. In an in vitro model of differentiated, primary human skeletal muscle myoblast cells, we demonstrate basal membrane expression and drug efflux activity of MRP1, which contributes to reducing intracellular statin accumulation. Furthermore, we show that expression of human OATP2B1 in human skeletal muscle myoblast cells by adenoviral vectors increases intracellular accumulation and toxicity of statins and such effects were abrogated when cells overexpressed MRP1. These results identify key membrane transporters as modulators of skeletal muscle statin exposure and toxicity.

Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation

Statins, used to treat hypercholesterolemia, are one of the most frequently prescribed drug classes in the developed world. However, a significant proportion of users suffer symptoms of myotoxicity, and currently, the molecular mechanisms underlying myotoxicity remain ambiguous. In this study, Saccharomyces cerevisiae was exploited as a model system to gain further insight into the molecular mechanisms of atorvastatin toxicity. Atorvastatin-treated yeast cells display marked morphological deformities, have reduced cell viability and are highly vulnerable to perturbed mitochondrial function. Supplementation assays of atorvastatin-treated cells reveal that both loss of viability and mitochondrial dysfunction occur as a consequence of perturbation of the sterol synthesis pathway. This was further investigated by supplementing statin-treated cells with various metabolites of the sterol synthesis pathway that are believed to be essential for cell function. Ergosterol, coenzyme Q and a heme precursor were all ineffective in the prevention of statin-induced mitochondrial disruption and cell death. However, the addition of geranylgeranyl pyrophosphate and farnesyl pyrophosphate significantly restored cell viability, although these did not overcome petite induction. This highlights the pleiotropic nature of statin toxicity, but has established protein prenylation disruption as one of the principal mechanisms underlying statin-induced cell death in yeast.

Drug Transporters: Recent Advances and Therapeutic Applications

Drug Transporters: Recent Advances and Therapeutic Applications

Towards companion diagnostics for the management of statin therapy

Statins are the most commonly prescribed drugs in the world and are established first-line therapy for cardiovascular disease. Statin toxicity is related to dose, age, gender, ethnicity, body mass, renal and endocrine function and also to concomitant medications - particularly those that inhibit cytochrome P450 3A4. This review describes the tests used before initiation of statin therapy, to establish their efficacy and to monitor their principal side effects. Lipids and apolipoproteins are used to measure efficacy and compliance, whereas transaminases and creatine kinase are used to measure toxicity. Guidelines agree in general, but differ in the details of measurement of baseline levels, action limits and management strategies for statin toxicity. Genetic factors are relevant to both the efficacy and the toxicity of statin therapy, with efficacy being associated with polymorphisms in lipid-related genes, whereas a function-related polymorphism in the organic anion transporting polypeptide 1B1 (OATP1B1; SLCO1B1) is associated with 60% of the cases of myopathy with high-dose simvastatin. Although basic efficacy and safety panels for the initiation and monitoring of statin therapy are well established, controversy remains about the need for ancillary diagnostics in patients and to which patient groups these should be applied.

Investigation of gene Expression in C2C12 Myotubes Following simvastatin Application and Mechanical Strain

The 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective prescribed drugs for lowering serum cholesterol; however, although statins are extremely safe medications and have brought significant benefits to patients with hypercholesterolemia, they have been shown to produce myalgia, cramps, exercise intolerance and fatigue. The aim of the study was to investigate the molecular mechanisms that may mediate statin myopathy. We used DNA microarray analysis to examine the changes in gene expression profiles induced by 1 hour and 6 hours of statin treatment on differentiated C(2)C(12) myotubes. Four genes were selected for analysis at the protein level using Western blot analysis on myotubes treated with statin with or without additional mechanical stretching. Eighty-five genes exhibited more than a 2-fold up- or down-regulation in expression, of which 46 have known biological functions related primarily to transmembrane transport, signal transduction, cell growth/maintenance, protein metabolism, or apoptosis. At protein level, three of the four proteins were induced (Adrb1, Socs4 and Cflar) and one was repressed (Birc4). Changes in protein expression largely mirrored the changes in their corresponding transcripts, although the fold-change was less dramatic. The addition of imposed muscle fiber stretching did not exacerbate the expression of these genes at the protein level with the exception of Cflar, a pro-apoptotic protein. These data suggested that alterations in the expressions of some statin-regulated genes could be causative factors for statin toxicity in muscle. Repression of the anti-apoptosis gene (Birc4) and activation of the pro-apoptosis gene (Cflar) indicated that cell death may play an important role in statin-induced myopathy.

LDL reduction: How low should we go and is it safe?

High-dose statin therapy or combination statin treatment is necessary for most patients to achieve aggressive low-density lipoprotein cholesterol goals. Adding ezetimibe or bile acid sequestrants appears unlikely to increase the risk of myopathy. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be reasonably safe, the safety of combination with high-dose statins has yet to be determined. To enhance patient outcomes, attention must be paid to characteristics that predict muscle and hepatic statin toxicity when considering using high-dose statin or combination statin therapy.

Inhibition of Macrophage Phagocytotic Activity by a Receptor-targeted Polymer Vesicle-based Drug Delivery Formulation of Pravastatin

Ruptures of macrophage-rich atherosclerotic plaques in the coronary arteries are the main reason for heart attack. Targeted therapeutic interventions with an inhibitory effect on the macrophages promise to be beneficial, but currently available drugs such as statins achieve event reductions of only 30%. Dose-limiting adverse effects in remote organs prohibit achieving higher drug levels known to have strong inhibitory effects on macrophages. Receptor-specific targeting using statin-loaded nanometer-sized triblock copolymer vesicles with targeting moieties might allow high-dose treatment for improved efficacy, while minimizing toxicity in other cells. Vesicle uptake by target cells but not other cell types and slow intracellular content release was observed. A major improvement in biologic efficacy was observed for polymer vesicles compared to free drug, whereas no increased cytotoxicity was observed in muscle cells. Such high-dose, targeted therapy of statins through cell-specific polymer vesicles allows novel treatment paradigms not only for atherosclerosis, but appears promising for a wide range of drugs and diseases.

Tendinous disorders attributed to statins: A study on ninety‐six spontaneous reports in the period 1990–2005 and review of the literature

To date, statins have more often been considered a safe medication. However, with the wider use of statins, severe side effects have also been reported to occur in statin-treated patients, especially myositis and rhabdomyolysis. Currently, however, statin-associated tendon impairment has only been described anecdotally. The aim of this retrospective study was to evaluate tendon manifestations occurring in statin-treated patients. All reports in which a statin was listed spontaneously as a causative suspect medication of tendon complications in the network of the 31 French Pharmacovigilance Centers from 1990-2005 were included in this study. Data collection included patient characteristics and tendon adverse effects (time to onset of adverse effects, pattern, site of injury, and outcome). The percentage of the reports was further calculated for each statin. Data were collected from 96 patients with a median age of 56 years; patients exhibited tendinitis (n = 63) and tendon rupture (n = 33). Tendinopathy more often occurred within the first year after statin initiation (59%). Tendon manifestations were related to atorvastatin (n = 35), simvastatin (n = 30), pravastatin (n = 21), fluvastatin (n = 5), and rosuvastatin (n = 5). Statin was reinitiated in 7 patients, resulting in recurrence of tendinopathy in all cases. Our series suggests that statin-attributed tendinous complications are rare, considering the huge number of statin prescriptions. We suggest that prescribers should be aware of tendinous complications related to statins, particularly in risky situations, including physical exertion and association with medications known to increase the toxicity of statins.

Statin toxicity: a situation that mimics viral hepatitis

A case is presented involving a female patient who experienced rhabdomyolysis following high-dose therapy with a statin. Acute renal failure was a complicating factor necessitating the use of hemodialysis. The patient recovered fully within about 6 weeks.

Ageing and oxidative stress: a role for dolichol in the antioxidant machinery of cell membranes?

Dolichol is a polyprenol compound broadly distributed in membranes, biosynthetized by the general isoprenoid pathway from acetate via mevalonate and farnesyl pyrophosphate. Dolichol lays inside the membrane between the two leaflets of the lipid bilayer very close to the tail of phospholipid fatty acids. No definite catabolic pathways for this molecule have yet been identified. Evidence is produced that dolichol levels increase dramatically with increasing age; that anti-ageing caloric restriction retards this age-associated change; that dolichol may act as a radical scavenger of peroxidized lipids belonging to the cell membranes. In view of the polyunsaturated fatty acids (PUFA), dolichol and Vitamin E location and stechiometry, it is proposed that molecules might interact each-other to form a highly matched free-radical-transfer chain, whose malfunctioning might be involved in statin toxicity and neurodegenerative diseases.

Musculoskeletal features of disorders of lipid metabolism and multicentric reticulohistiocytosis.

Musculoskeletal features of hyperlipidemia are well known, although rarely encountered by rheumatologists. New data have been collected on the beneficial and adverse effects of lipid-lowering drugs, which are of interest to rheumatologists. Multicentric reticulohistiocytosis is a rare systemic disorder of which joint involvement is an important and frequent feature. Recent advances in its pathophysiology and management have been made. Little has been added to the knowledge about the musculoskeletal features of hyperlipidemia in the recent literature. In contrast, the interest in fenofibrate for treating hyperuricemia in patients with lipid disorders or in those intolerant of allopurinol has been further supported. Muscle toxicity of statins continue to retain attention, and the ability of these drugs to induce low-grade myopathy, without increasing serum creatine kinase, has been defended. Multicentric reticulohistiocytosis has been the subject of a number of articles, including reports on the efficacy of cyclosporine and of etanercept in one patient each. Several issues of therapeutic importance are discussed in this brief review.

Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses

The mevalonate pathway produces many critical substances in cells, including sterols essential for membrane structure and isoprenoids vital to the function of many membrane proteins. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the mevalonate pathway. Because cholesterol is a product of this pathway, HMG-CoA reductase inhibitors (statins) are used to treat hypercholesterolemia. Statins are also toxic to several malignancies, including acute myeloid leukemia (AML). Although this toxicity has been attributed to the inhibition of Ras/Rho isoprenylation, we have previously shown that statin toxicity in primary AML cells (AMLs) does not correlate with Ras isoprenylation or with activating Ras mutations. In other studies, we have shown that hypoxic and oxidant injuries induce cholesterol increments in renal tubule cells and that statins sensitize these cells to injury by blocking protective cholesterol responses. We now demonstrate that exposing particular AMLs to radiochemotherapy induces much greater cellular cholesterol increments than those seen in similarly treated normal bone marrow. Treatment of these AMLs with mevastatin or zaragozic acid (which inhibits cholesterol synthesis but not isoprenoid synthesis) attenuates the cholesterol increments and sensitizes cells to radiochemotherapy. The extent of toxicity is affected by the availability of extracellular lipoproteins, further suggesting that cellular cholesterol is critical to cell survival in particular AMLs. Because zaragozic acid does not inhibit isoprenoid synthesis, these data suggest that cholesterol modulation is an important mechanism whereby statins exert toxic effects on some AMLs and that cholesterol modulators may improve therapeutic ratios in AML by impacting cholesterol-dependent cytoresistance.

Reversal of statin toxicity to human lymphocytes in tissue culture.

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are widely used to inhibit biosynthesis of cholesterol in individuals with elevated serum levels of this risk factor for cardiovascular disease. We find that statins are toxic to human lymphocytes in cell culture at concentrations less than 0.1 microg/ml. Addition of their own plasma reverses this toxicity in some, but not all, individuals. Addition of coenzyme Q10 (CoQ10) with plasma is more effective than plasma alone in reversing toxicity in some individuals. Apparently, two factors are required to reverse the cellular toxicity of statins: CoQ10 and a plasma factor found in a subset of individuals. These observations may provide the basis for a method to assess individual susceptibility to statin toxicity and to predict which individuals may benefit from supplements of CoQ10.

Safety and Efficacy of HMG‐CoA Reductase Inhibitors for Treatment of Hyperlipidemia in Patients with HIV Infection

To assess the efficacy and safety of HMG-CoA reductase inhibitors (statins) in patients with human immunodeficiency virus (HIV) infection and hyperlipidemia. Retrospective analysis. HIV clinic. Twenty-six HIV-infected patients with hyperlipidemia. Five patients received pravastatin, 13 lovastatin, 10 simvastatin, and 2 atorvastatin (total 30 courses). Reductions in cholesterol and triglycetides were used to assess efficacy; creatine kinase (CK), liver enzymes, and myalgia were markers of statin toxicity. After a median of 8.2 and 7.2 months of treatment, the agents collectively reduced median baseline total cholesterol 27% (354 to 263 mg/dl) and triglycerides 15% (513 to 438 mg/dl), respectively. Two patients, one with marked CK elevations, experienced myalgias with lovastatin, and two experienced transaminase elevations 3 or more times the upper limit of normal. Statins are effective in reducing total cholesterol and triglycerides in HIV-infected patients, although lipid levels infrequently return to normal. Lovastatin should be avoided in patients receiving concomitant drugs that may potentiate skeletal muscle toxicity with this agent.