Statin Toxicity Research Articles

The Toxicity and Biological Functions of Statins During Treatments

Cardiovascular morbidity and mortality are reduced by statins, which are drugs that lower cholesterol and reduce LDL-c. Statins function by competitively blocking the primary rate-limiting enzyme in HMG-CoA reductase, inhibiting it so that no substrate can enter and no HMG-CoA can be converted to mevalonic acid. Statins are by far the mainstay of majority and minority prevention of atherosclerotic cardiovascular disease, but they have also been linked to a variety of side effects. Statin therapy should be discontinued because of muscle symptoms associated with it and the development of new-onset type 2 diabetes as a side effect of statins is a serious issue and the pathogenesis of it is still unclear. This paper focuses on the biological function of statins and their toxicity, i.e. the mechanisms responsible for the adverse effects. It is intended to inform the study of the mechanisms of toxicity episodes of statins. Some of the mechanisms of toxicity onset of statins cannot be determined at this time, various patient populations could be studied in future studies to explore the side effects of statins.

Pharmacogenomic Variants Affecting Statins Response in Sri Lanka

Pharmacogenomic variants can influence the efficacy and toxicity of statins, which are commonly prescribed medications for managing cholesterol levels and reducing the risk of cardiovascular events. Statins work by inhibiting HMG-CoA reductase, an enzyme involved in cholesterol synthesis. Ranasinghe and colleagues investigated the diversity of pharmacogenetic variants of statins among Sri Lankans. They compared the minor allele frequencies (MAFs) of 426 Sri Lankans with other populations. They observed the following MAFs in common genes usually associated with statins response and toxicity. The MAF of SLCO1B1*5 (rs4149056 [T>C]) was 18.19% (95% CI: 14.53-21.85), MAFs of CYP2C9*2 (rs1799853 [C>T]) and CYP2C9*3 (rs1057910 [A>C]) were 2.58% (95% CI: 1.08-4.08) and 10.30% (95% CI: 7.75-13.61), respectively, MAFs of rs2231142 (G>T) (ABCG2), rs7412 (C>T) (APOE) and rs20455 (A>G) (KIF6) variants were 10.68% (95% CI: 7.76-13.60), 3.52% (95% CI: 1.77-5.27) and 50.7% (95% CI: 45.96-55.45), respectively. They found the frequency of two variants higher in the Sri Lankan population compared to the Western and other Asian populations (rs20455 (A>G), CYP2C9*3 (A>C) and SLCO1B1*5 (T>C)). They concluded that genetic polymorphisms affecting efficacy of statins (KIF6 [rs20455], CYP2C9*3) and increased risk of statin-induced myotoxicity (SLCO1B1*5 and CYP2C9*3) were prevalent in higher frequencies among Sri Lankans compared with Western populations. Pharmacogenomics. 2023 Oct;24(15):809-819. doi: 10.2217/pgs-2023-0149.

A change in risk assessment for treatment with statins in patients with familial hypercholesteremia and Gilbert's syndrome

Abstract Background Gilbert’s Syndrome (GS) is a heredity disease that mildly increases serum unconjugated bilirubin. GS is usually asymptomatic and considered to be benign. It is postulated to be present in 10-16% of the population but the exact incidence is unknown since it is usually an incidental finding that goes under diagnosed and under-reported. Conversely, heterozygous familial (FH) hypercholesteremia, estimated to be present in 1 in 250, is responsible for significant morbidity and mortality and never ignored. Patients with FH are especially at risk for atherosclerotic cardiovascular disease (ASCVD) due to the cumulative effect of high cholesterol starting at a young age. Recent studies report that mildly elevated serum bilirubin (especially the UGT1A1*28 allele), in patients with concurrent GS and FH, is protective against ASCVD. The deleterious effect of one liver mutation may be offset by the beneficial effect of the second mutation resulting in an inverse relationship between the two diseases. Due to that association, statins may be contraindicated in patients with concurrent FH and GH because they are more susceptible to toxicity and adverse events. Purpose Patients with coexisting FH and GS are postulated to have innate cardioprotection and therefore, treatment with statins may be unnecessary and should be avoided due to an increased risk for drug toxicity and intolerable adverse events. Methods This was a systematic review of 31 peer-reviewed publications identified by using databases: EBSCO Discovery, World Cat, PubMed, OVID, Google Scholar, Springer, Theime, Elsevier, Science Direct, and Cochrane Collaboration. Publications ranged from 2006-2021 and included subjects ages 18-80 and bench studies using Gunn rats. The quality of evidence was analyzed and evaluated. Results Recent retrospective and prospective studies indicate that mildly elevated serum bilirubin, in patients with concurrent GS and FH, is protective against ASCVD. Consequently, this population may not need statin therapy and may be more susceptible to statin toxicity and intolerable adverse events. Conclusion GS is postulated be innately cardioprotective for ASCVD. The identification of patients with concurrent FH and GS is not mainstream and is overdue. These are not uncommon diseases and their co-existence has been underestimated because GS is considered benign and underreported. The potential exists for patients with FH and silent Gilbert’s Syndrome to be overtreated or unnecessarily treated with statins. Medications that inhibit UDP-glucuronosyltranferase-enzyme activity and UG1A1 mediated glucuronidation may lead to toxicity and intolerable adverse events. Studies have shown an adverse relationship between statins and increased bilirubin. It is recommended that both FH and Gilbert’s Syndrome be routinely screened for in pediatric and adult populations, especially prior to statin prescribing.

Pharmacogenomic variants affecting efficacy and toxicity of statins in a south Asian population from Sri Lanka.

Aim: To describe the diversity of pharmacogenetic variants of statins among Sri Lankans. Materials & methods: Variant data of relevant genes were obtained from an anonymized database of 426 Sri Lankans. Minor allele frequencies (MAFs) were compared with published data from other populations. Results: The MAF of SLCO1B1*5 (rs4149056 [T>C]) was 18.19% (95% CI: 14.53-21.85). MAFs of CYP2C9*2 (rs1799853 [C>T]) and CYP2C9*3 (rs1057910 [A>C]) were 2.58% (95% CI: 1.08-4.08) and 10.30% (95% CI: 7.75-13.61), respectively. MAFs of rs2231142 (G>T) (ABCG2), rs7412 (C>T) (APOE) and rs20455 (A>G) (KIF6) variantswere 10.68% (95% CI: 7.76-13.60), 3.52% (95% CI: 1.77-5.27) and 50.7% (95% CI: 45.96-55.45), respectively. Compared with western/other Asian populations, rs20455 (A>G), CYP2C9*3 (A>C) and SLCO1B1*5 (T>C) variants were significantly higher in Sri Lankans. Conclusion: Variants that affect efficacy of statins (KIF6 [rs20455], CYP2C9*3) and increase risk of statin-induced myotoxicity (SLCO1B1*5 and CYP2C9*3) were prevalent in higher frequencies among Sri Lankans compared with western populations.

Differential effects of OATP2B1 on statin accumulation and toxicity in a beta cell model

An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells via adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.

Systems assessment of statins hazard: Integrating in silico prediction, developmental toxicity profile and transcriptomics in zebrafish

Statins are prescribed widely as lipid-lowering agents. However, statins are associated with an increased harmful risk on public health and the ecosystem. Little is known about statins’ toxicity on biological development and the underlying molecular mechanisms. We exposed zebrafish embryos to a series of statins to evaluate their development toxicity. Statins-induced embryonic developmental defects in a concentration-dependent manner. 72 h LC50 values for lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, and pravastatin were 0.01 μM, 0.04 μM, 1.93 μM, 37.28 μM, 79.29 μM, and 2170 μM, respectively. Moreover, the expression of genes involved in heart contraction, calcium ion binding, transcription factors, nucleus, and G protein-coupled receptor signaling pathway was altered by statins. The early growth response gene (egr4) and transcription factor genes (fosab and fosb) were screened as potential toxicity targets due to their significant upregulation based on protein-protein interaction (PPI) and drug-gene interaction network analysis. Finally, the ecotoxicity profile of statins was predicted by in silico method, and statins were high or moderate risk to aquatic organisms. We provide a systems toxicology strategy to explore the toxicity of statins and illustrate the potential mechanisms of action.

Statin Intolerance and Noncompliance: An Empiric Approach

Statin Intolerance and Noncompliance: An Empiric Approach

Association between CYP3A5 Polymorphism and Statin-Induced Adverse Events: A Systemic Review and Meta-Analysis.

Purpose: Cytochrome P450 (CYP) is involved in the metabolism of statins; CYP3A5 is the main enzyme responsible for lipophilic statin metabolism. However, the evidence of the association between CYP3A5*3 polymorphism and the risk of statin-induced adverse events remains unclear. Therefore, this study aimed to perform a systematic review and meta-analysis to investigate the relationship between the CYP3A5*3 polymorphism and the risk of statin-induced adverse events. Methods: The PubMed, Web of Science, and EMBASE databases were searched for qualified studies published until August 2020. Observational studies that included the association between statin-induced adverse events and the CYP3A5*3 polymorphism were reviewed. The odds ratios (ORs) and 95% confidence intervals (CIs) were evaluated to assess the strength of the relationship. The Mantel–Haenszel method was used to provide the pooled ORs. Heterogeneity was estimated with I2 statistics and publication bias was determined by Begg’s and Egger’s test of the funnel plot. Data analysis was performed using Review Manager (version 5.4) and R Studio (version 3.6). Results: In total, data from 8 studies involving 1614 patients were included in this meta-analysis. The CYP3A5*3 polymorphism was found to be associated with the risk of statin-induced adverse events (*3/*3 vs. *1/*1 + *1/*3: OR = 1.40, 95% CI = 1.08–1.82). For myopathy, the pooled OR was 1.30 (95% CI: 0.96–1.75). The subgroup analysis of statin-induced myopathy revealed a trend, which did not achieve statistical significance. Conclusions: This meta-analysis demonstrated that the CYP3A5*3 polymorphism affected statin-induced adverse event risk. Therefore, CYP3A5 genotyping may be useful to predict statin toxicity.

Simvastatin Toxicity Induces Mitochondrial Dysfunction in Rat Skeletal Muscle

Background: Statins are the class of drugs that are widely used for lowering LDL cholesterol and as primaryand secondary prevention to cardiovascular disease. However, the widespread use of statins is constrained bythe presence of toxicity or intolerance, which affects drug control rates. The toxicity or intolerance of statinsranges from 10-15%. The most common statin toxicity is statin-associated muscle symptoms (SAMS). Theunderlying mechanisms of SAMS involve the disruption of mitochondrial biogenesis, potential membranechanges, reduced number of mitochondria, and changes in protein oxidative activity due to the accumulationof ROS in cells and tissues. The disruption of mitochondrial biogenesis can be marked by a decrease ofperoxisome proliferator-activated receptor co-activator gamma (PGC-1a). This study aimed to determine theeffect of simvastatin on skeletal muscle PGC-1a.Methods: Sixteen female Wistar rats (8-10 weeks of age) were randomized into 2 groups: (1) control group(n=8), and (2) simvastatin group(n=8). For 30 days, the simvastatin group was exposed to simvastatinat a dose of 10 mg/kg/day. Meanwhile, the control group animals only received 0.5% methyl cellulose.Gastrocnemius muscles were collected and PGC-1a levels were evaluated by using ELISA Kit.Results: Following 30 days of treatment, a significantly lower level of skeletal muscle PGC-1awas observedin the simvastatin group compared to the control group (p = .026).Conclusion: Our finding indicates that administration of simvastatin at a dose of 10 mg/kg/day for 30 daysmay decrease skeletal muscle PGC-1a leading to mitochondrial dysfunction in rat skeletal muscle.

Simvastatin Toxicity Induces Mitochondrial Dysfunction in Rat Skeletal Muscle

Background: Statins are the class of drugs that are widely used for lowering LDL cholesterol and as primary and secondary prevention to cardiovascular disease. However, the widespread use of statins is constrained by the presence of toxicity or intolerance, which affects drug control rates. The toxicity or intolerance of statins ranges from 10-15%. The most common statin toxicity is statin-associated muscle symptoms (SAMS). The underlying mechanisms of SAMS involve the disruption of mitochondrial biogenesis, potential membrane changes, reduced number of mitochondria, and changes in protein oxidative activity due to the accumulation of ROS in cells and tissues. The disruption of mitochondrial biogenesis can be marked by a decrease of peroxisome proliferator-activated receptor co-activator gamma (PGC-1a). This study aimed to determine the effect of simvastatin on skeletal muscle PGC-1a.Methods: Sixteen female Wistar rats (8-10 weeks of age) were randomized into 2 groups: (1) control group (n=8), and (2) simvastatin group(n=8). For 30 days, the simvastatin group was exposed to simvastatin at a dose of 10 mg/kg/day. Meanwhile, the control group animals only received 0.5% methyl cellulose. Gastrocnemius muscles were collected and PGC-1a levels were evaluated by using ELISA Kit.Results: Following 30 days of treatment, a significantly lower level of skeletal muscle PGC-1awas observed in the simvastatin group compared to the control group (p = .026). Conclusion: Our finding indicates that administration of simvastatin at a dose of 10 mg/kg/day for 30 days may decrease skeletal muscle PGC-1a leading to mitochondrial dysfunction in rat skeletal muscle

HMG-CoA Reductase Inhibitors (Statins) and their Drug Interactions Involving CYP Enzymes, P-glycoprotein and OATP Transporters-An Overview

Hydroxymethyl glutaryl-CoA (HMG-CoA) reductase inhibitors (Statins) are used to treat dyslipidemia. Generally, the statins are the substrates of CYP enzymes, P-glycoprotein (P-gp), and organic anion transporting polypeptides transporters (OATP1B1). This review article focuses on the clinical significance of statins, and their interactions in real practice. The databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, Cochrane Library, Directory of open access journals (DOAJ), and reference lists were searched to identify relevant articles. Most of the drug interactions of statins result in elevated plasma concentrations and toxicity of statins due to the inhibition of CYP3A4, P-gp and/or OATP1B1 transporters. The toxicity of statins includes myopathy, rhabdomyolysis, elevated liver enzymes, acute kidney injury, and diabetes. The statins like simvastatin, lovastatin, and atorvastatin are substrates of CYP3A4 enzyme and P-glycoprotein and their concomitant use with the drugs inhibiting or inducing them would result in changes in plasma concentrations and toxicity/efficacy. However, the statins like pravastatin, rosuvastatin and pitavastatin are not substrates of CYP enzymes and hence the concomitant use of CYP inhibitors or inducers does not affect them. Almost all the statins are the substrates of OATP1B1 transporter, and the co-prescription of inhibitors of OATP1B1 elevates the plasma concentrations and muscle toxicity of statins. Understanding the interacting potential of each statin will enable the prescribers, pharmacists, and other health care professionals to use statins effectively without compromising patient safety.

PROTECTIVE EFFECT OF QUERCETIN AGAINST STATINS INDUCED-HEPATOTOXICITY IN CELL LINE

Objective: Statins are the most prescribed lipid lowering agents and consequently they prevent obstructive cardiovascular events in the world. Severe adverse effects of statins, involving myopathy and hepatotoxicity, sometimes limit their usage as lipid lowering agents. We now investigate the toxicity of statins and prove the protective effect of quercetin against statins toxicity in cell line. Methods: Human hepatocellular carcinoma cells HepG2 were used in this study were cultured at 37℃ in 5% CO2, in Roswell Park Memorial Institute medium (RPMI 1640) and were supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, and 100 mg/mL streptomycin. HepG2 cells were cultured with some of statins as Atorvastatin, Simvastatin and Rosuvastatin with 10µM concentration with and without pretreatment with 10, 20, 40µM quercetin 4 hours before the addition of statins, then cell line was incubated for 24 and 48 hours. Toxicity of statins was determined by cell viability assay (MTT assay), ALT&AST level assay, lipid peroxidation assay by Malondialdehyde (MDA) and Immunofluorescence staining assay using DAPI. Results: ALT&AST levels were significantly increased after the addition of statins in HepG2 cells when compared with the control group (DMSO 0.1%), and ALT&AST levels were significantly decreased with pretreatment of the cells with quercetin 4 hours before the addition of statins in a dose-dependent manner when compared with statin group. Cell viability percentage (MTT concentration) was decreased significantly after the addition of statins to HepG2 cells when compared with the control group, and MTT concentration was significantly increased with pretreatment of the cells with quercetin 4 hours before the addition of statins in a dose-dependent manner when compared with statin group. MDA concentrations increased significantly after the addition of statins to HepG2 cells when compared with the control group, and decreased when the cells were pretreated with quercetin 4 hours before the addition of statins in a dose-dependent manner when compared with statin group. Statins cause cellular oxidative damage by liberating reactive oxygen species, and the cellular damage was prevented when the cells pretreated with quercetin 4 hours before addition of statins. Conclusions: We found that, quercetin shall protect HepG2 cells from statins-induced hepatotoxicity with 10, 20, 40µM concentrations without significant difference between 20 and 40µM concentrations, and may be developed as a therapeutic agent for possible statins toxicity.

Resveratrol for protection against statin toxicity in C2C12 and H9c2 cells.

Statins are among the most commonly prescribed drugs for the treatment of high blood cholesterol. Myotoxicity of statins in certain individuals is often a severe side effect leading to withdrawal. Using C2C12 and H9c2 cells, both exhibiting characteristics of skeletal muscle cells, we addressed whether resveratrol (RSV) can prevent statin toxicity. Statins decreased cell viability in a dose and time-dependent manner. Among the five statins tested, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin, simvastatin is the most toxic one. Simvastatin at 10 µM caused about 65% loss of metabolic activity as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays in C2C12 cells or H9c2 cells. Inhibition of metabolic activity correlates with an increase in caspase activity. RSV was found to protect H9c2 cells from simvastatin-induced activation of caspase-3/7. However, such protection was not found in C2C12 cells. This cell type-dependent effect of RSV adds to the complexity in muscle cell toxicity of statins.

Statins affect human glioblastoma and other cancers through TGF-β inhibition.

The cholesterol-lowering statins have known anti-cancer effects, but the mechanisms and how to utilize statins in oncology have been unclear. We noted in the CellMiner database that statin activity against cancer lines correlated with higher expression of TGF-β target genes such as SERPINE1 and ZYX. This prompted us to assess whether statins affected TGF-β activity in glioblastoma (GBM), a cancer strongly influenced by TGF-β and in dire need of new therapeutic approaches. We noted that statins reduced TGF-β activity, cell viability and invasiveness, Rho/ROCK activity, phosphorylation and activity of the TGF-β mediator Smad3, and expression of TGF-β targets ZYX and SERPINE1 in GBM and GBM-initiating cell (GIC) lines. Statins were most potent against GBM, GIC, and other cancer cells with high TGF-β activity, and exogenous TGF-β further sensitized mesenchymal GICs to statins. Statin toxicity was rescued by addition of exogenous mevalonolactone or geranylgeranyl pyrophosphate, indicating that the observed effects reflected inhibition of HMG CoA-reductase by the statins. Simvastatin significantly inhibited the growth of subcutaneous GIC grafts and prolonged survival in GIC intracranially grafted mice. These results indicate where the statins might best be applied as adjunct therapies in oncology, against GBM and other cancers with high TGF-β activity, and have implications for other statin roles outside of oncology.

Statin Toxicity.

There is now overwhelming evidence to support lowering LDL-c (low-density lipoprotein cholesterol) to reduce cardiovascular morbidity and mortality. Statins are a class of drugs frequently prescribed to lower cholesterol. However, in spite of their wide-spread use, discontinuation and nonadherence remains a major gap in both the primary and secondary prevention of atherosclerotic cardiovascular disease. The major reason for statin discontinuation is because of the development of statin-associated muscle symptoms, but a range of other statin-induced side effects also exist. Although the mechanisms behind these side effects have not been fully elucidated, there is an urgent need to identify those at increased risk of developing side effects as well as provide alternative treatment strategies. In this article, we review the mechanisms and clinical importance of statin toxicity and focus on the evaluation and management of statin-associated muscle symptoms.

Retrospective evaluation of statin prescription in the elderly.

Statins are one of the most commonly prescribed medications in Australia. Although the cardioprotective effects of statins are well documented, questions remain regarding their risk-benefit profile in elderly adults, especially those with limited life expectancies. To describe the prevalence and pattern of statin use in elderly patients admitted to a General Medicine Unit. We retrospectively reviewed medical records of patients aged ≥80 years who were admitted to the General Medical Unit at Monash Medical Centre between 1 January 2015 and 30 June 2015. Patients receiving statin therapy prior to admission were identified and included. Data including patient demographics, indication for statin, comorbidities, co-prescription of interacting medications, presence of muscle-related toxicity and any change to statin prescription were collected and described. Of 852 patients admitted to hospital, 359 (42%) were taking statins prior to admission. Statins were used for the secondary prevention of cardiovascular disease in 63% of patients and for primary prevention in 24%. Most patients were taking high- (16%) or medium-intensity statins (78%); 46% of patients were co-prescribed medications with the potential to increase the risk of statin toxicity. Statins were discontinued in 16% of patients; however, the majority of patients had no change to their statin prescription. Muscle-related toxicity was documented in 4% of patients. Statin use and the co-prescription of potentially interacting medications are common in elderly adults admitted to hospital. Statin prescription in elderly patients with multiple comorbidities is rarely reviewed unless directly relevant to their admission diagnosis.

Statins: Adverse reactions, oxidative stress and metabolic interactions.

Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are currently the most effective lipid-lowering drugs, effectively reducing the plasma total cholesterol and low-density lipoprotein, while also decreasing three triacylglycerols and increasing plasma high-density lipoprotein to a certain extent. However, the excessive or long-term use of statins can cause in vitro cytotoxicity, in vivo liver injury, liver necrosis, kidney damage, and myopathy in both human beings and animals. Many studies indicate that oxidative stress is involved in the various toxicities associated with statins, and various antioxidants have been evaluated to investigate their protective roles against statin-induced liver, kidney, and muscle toxicities. Widespread attention has been given to statin-induced oxidative stress, with and without the use of other drugs. Much of the information about the mechanism for this reduction comes from cell culture and in experimental animal studies. The primary focus of this article is to summarize the research progress associated with oxidative stress as a plausible mechanism for statin-induced toxicity, as well as its metabolic interactions. This review summarizes the research conducted over the past five years into the production of reactive oxygen species, oxidative stress as a result of statin treatments, and their correlation with statin-induced toxicity and metabolism. Statin-induced metabolism involves various CYP450 enzymes, which provide potential sites for statin-induced oxidative stress, and these metabolic factors are also reviewed. The therapeutics of a variety of compounds against statin-induced organ damage based on their anti-oxidative effects is also discussed to further understand the role of oxidative stress in statin-induced toxicity. This review sheds new light on the critical roles of oxidative stress in statin-induced toxicity and prevention of this oxidative damage, as well as on the contradictions and unknowns that still exist regarding statin toxicity and the cellular effects in terms of organ injury and cell signaling pathways.

Interactions Between ABCB1 Genotype and Preoperative Statin Use Impact Clinical Outcomes Among Breast Cancer Patients.

Multiple clinical trials investigate statins' effects in breast cancer. The ABCB1 genotype appears to influence statin response and toxicity in the cardiovascular setting. This exploratory study aimed to investigate the interplay between preoperative statin use, ABCB1 genotype, and tumor-specific expression of the statin target 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in breast cancer. Preoperative statin use, ABCB1 C3435T genotype, and HMGCR expression in relation to outcome were analyzed in 985 primary breast cancer patients from a population-based prospective cohort in Sweden from 2002 to 2012. Preoperative statin use (n = 80) was not associated with ABCB1 C3435T genotype (n = 576), HMGCR expression (n = 848), or clinical outcomes. ABCB1 C3435T TT-carriers had lower risk of breast cancer events than any C-carriers (adjusted hazard ratio (HRadj) 0.74; 95%CI 0.49, 1.12), but only in non-statin users (Pinteraction = 0.042). Statin users with TT genotype had higher risk of distant metastasis (HRadj 4.37; 95%CI 1.20, 15.91; Pinteraction = 0.009) and shorter overall survival than other patients (HRadj 3.77; 95%CI 1.37, 10.39; Pinteraction = 0.019). In conclusion, there were nominally significant interactions between ABCB1 genotype and preoperative statin use on clinical outcomes, while preoperative statin use was not associated with outcomes. Since this is an exploratory study of the impact of the ABCB1 genotype in relation to statin use and clinical outcomes in the breast cancer setting, the results should be interpreted with caution and warrant replication in an independent cohort, preferably in a randomized setting. Since statin use is common in breast cancer patients, it would be of interest to further elucidate the clinical impact of the ABCB1 genotype in breast cancer.

Phenotype-Specific Response of Circulating miRNAs Provides New Biomarkers of Slow or Fast Muscle Damage.

Skeletal muscle is a heterogeneous tissue composed of a continuum of contracting fibers ranging from slow-type to fast-type fibers. Muscle damage is a frequent event and a susceptibility of fast-fibers to exercise-induced damage (EIMD) or statins toxicity has been reported. Biological markers of muscle damage such as creatine kinase (CK) are not fiber-type specific and new biomarkers are needed. Some microRNAs (miRNAs) are specific to the muscle tissue, can be found in the extracellular compartment and can rise in the plasma following muscle damage. Our aim was to identify whether a set of circulating miRNAs can be used as fiber-type specific biomarkers of muscle damage in a model of traumatic (crush) injuries induced either in the slow soleus (SOL) or in the fast extensor digitorum longus (EDL) muscles of rats. A subset of miRNAs composed of miR-1-3p, -133a-3p, -133b-3p, 206-3p, -208b-3p, 378a-3p, -434-3p, and -499-5p were measured by RT-PCR in non-injured SOL or EDL muscle and in the plasma of rats 12 h after damage induced to SOL or EDL. MiR-133b-3p, -378a-3p, and -434-3p were equally expressed both in SOL and EDL muscles. MiR-1-3-p and -133a-3p levels were higher in EDL compared to SOL (1.3- and 1.1-fold, respectively). Conversely, miR-206-3p, -208b-3p, and -499-5p were mainly expressed in SOL compared to EDL (7.4-, 35.4-, and 10.7-fold, respectively). In the plasma, miR-1-3p and -133a-3p were elevated following muscle damage compared to a control group, with no difference between SOL and EDL. MiR-133b-3p and -434-3p plasma levels were significantly higher in EDL compared to SOL (1.8- and 2.4-fold, respectively), while miR-378a-3p rose only in the EDL group. MiR-206-3p levels were elevated in SOL only (fourfold compared to EDL). Our results show that plasma miR-133b-3p and -434 are fast-fiber specific biomarkers, while miR-206-3p is a robust indicator of slow-fiber damage, opening new perspectives to monitor fiber-type selective muscle damage in research and clinic.

Facilitation of Ca2+ -induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment.

Mitochondrial redox imbalance and high Ca2+ uptake induce the opening of the permeability transition pore (PTP) that leads to disruption of energy-linked mitochondrial functions and triggers cell death in many disease states. In this review, we discuss the major results from our studies investigating the consequences of NAD(P)-transhydrogenase (NNT) deficiency, and of statins treatment for mitochondrial functions and susceptibility to Ca2+ -induced PTP. We highlight the aggravation of high fat diet-induced fatty liver disease in the context of NNT deficiency and the role of antioxidants in the prevention of statins toxicity to mitochondria.