SLCO1B1 c.388A>G Polymorphism Is Associated with HDL-C Levels in Response to Atorvastatin in Chilean Individuals

The use of statins as the preferred lipid-lowering therapy has clearly demonstrated its efficacy in the treatment of hypercholesterolemia, reducing also the risk of coronary events and cardiovascular disease mortality. In this study, we assessed single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene and their effect on atorvastatin response. We included 129 Chilean hypercholesterolemic patients undergoing 10 mg/day of atorvastatin therapy during 4 weeks. Lipid profile was determined before and after drug administration. Genotyping of SLCO1B1 rs4149056 (c.521T>C) SNP was performed with allele-specific polymerase chain reaction, whilst polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for genotyping the SLCO1B1 rs2306283 (c.388A>G) variant. After statin therapy, concentrations of TC, LDL-C and TG had a decrease from baseline (p < 0.05). Also, HDL-C levels increased (p < 0.05). Minor allele frequencies for the rs2306283 and rs4149056 variants were 0.547 and 0.136, respectively. LDL-C response to atorvastatin was not associated with the SLCO1B1 rs4149056 nor the rs2306283 polymorphisms (p > 0.05). However, the latter SNP was associated with HDL-C variability after atorvastatin medication (p = 0.02). This study indicates that LDL-C reduction following atorvastatin therapy is not influenced by the SNPs evaluated. In addition, the polymorphism rs2306283 at the SLCO1B1 gene determines greater HDL-C concentrations in response to atorvastatin medication in Chilean hypercholesterolemic subjects

Atorvastatin increases the expression of long non-coding rnas arsr and chrome in hypercholesterolemic patients: A pilot study

Atorvastatin is extensively used to treat hypercholesterolemia. However, the wide interindividual variability observed in response to this drug still needs further elucidation. Nowadays, the biology of long non-coding RNAs (lncRNAs) is better understood, and some of these molecules have been related to cholesterol metabolism. Therefore, they could provide additional information on variability in response to statins. The objective of this research was to evaluate the effect of atorvastatin on three lncRNAs (lncRNA ARSR: Activated in renal cell carcinoma (RCC) with sunitinib resistance, ENST00000424980; lncRNA LASER: lipid associated single nucleotide polymorphism locus, ENSG00000237937; and lncRNA CHROME: cholesterol homeostasis regulator of miRNA expression, ENSG00000223960) associated with genes involved in cholesterol metabolism as predictors of lipid-lowering therapy performance. Twenty hypercholesterolemic patients were treated for four weeks with atorvastatin (20 mg/day). The lipid profile was determined before and after drug administration using conventional assays. The expression of lncRNAs was assessed in peripheral blood samples by RT-qPCR. As expected, atorvastatin improved the lipid profile, decreasing total cholesterol, LDL-C, and the TC/HDL-C ratio (p < 0.0001) while increasing the expression of lncRNAs ARSR and CHROME (p < 0.0001) upon completion of treatment. LASER did not show significant differences among the groups (p = 0.50). Our results indicate that atorvastatin modulates the expression of cholesterol-related lncRNAs differentially, suggesting that these molecules play a role in the variability of response to this drug; however, additional studies are needed to disclose the implication of this differential regulation on statin response.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1171765 Direccion de Investigacion of the Universidad de La Frontera DI11-0063 Conicyt -Chile Doctoral Scholarshi

Acute and 28-day subchronic toxicity studies of mangiferin, a glucosylxanthone isolated from Mangifera indica L. stem bark.

Context: Pharmacological properties of mangiferin have been reported, but few studies have investigated mangiferin toxicity. Aims: To study the acute and 28-day toxicity effects of mangiferin in rodents. Methods: Single doses of mangiferin were administered by oral or i.p. route or were applied dermally to Sprague-Dawley rats and Balb/C mice. Clinical symptoms of animals were observed during 14 days after treatment. Animals also received single oral doses daily for 28 consecutive days. Blood biochemistry, hematology and pathology findings were reported. Results: In the acute study, no toxic effects were observed after dermal exposure to mangiferin 2000 mg/kg but transient dyspnea, flank position and piloerection were observed after oral administration to this xanthone. I.p. administration induced similar toxicity signs, but at the highest dose (2000 mg/kg) all mice, one female rat and one male rat died. Rats orally treated with mangiferin (250-1000 mg/kg) for 28 days did not show any abnormal clinical signs or hematology alterations, when compared to control group animals. Histopathological alterations like vacuolar degeneration, necrosis and increment of apoptosis of the acinar cells were observed in the exocrine pancreas of rats at 1000 mg/kg. This suggesting that exocrine pancreas was the target organ for mangiferin’s toxicity. Conclusions: These studies indicated that acute and subchronic toxicities of mangiferin for oral exposure are low

Farmacogenética aplicada al tratamiento de la leucemia linfoide aguda Pharmacogenetics applied to the treatment of acute lymphoid leukemia

Las enzimas de biotransformación y eliminación de los fármacos en pacientes con leucemia linfoide aguda tienen una acción determinante en el efecto terapéutico de los medicamentos antineoplásicos. La presencia y actividad de estos complejos enzimáticos está codificada genéticamente y sujeta a variaciones alélicas, cuyas frecuencias son variables en las diferentes poblaciones humanas. Este polimorfismo genético influye sobre la efectividad terapéutica de los medicamentos y condiciona la carencia de toxicidad o presencia de esta, que en ocasiones puede ser fatal. Las enzimas tiopurin-metil-transferasa, metilén-tetrahidrofolato-reductasa y glutatión-tranferasa son sistemas destoxificadores de algunos de los quimioterápicos empleados en el tratamiento de la leucemia linfoide aguda. En este trabajo se revisan las características genéticas de estas enzimas, la frecuencia de sus polimorfismos y las implicaciones clínicas de su expresión. De igual modo se discute la importancia y los beneficios del genotipaje previo al inicio del tratamiento, con el fin de modificar las dosis de los medicamentos para optimizar su efecto terapéutico y disminuir su toxicidad. La farmacogenética constituye un área de creciente interés que ha tenido un desarrollo considerable en los últimos años, su conocimiento e implementación nos colocará en el camino de la medicina personalizada.<br>The biotransformation and elimination enzymes of drugs in patients suffering from acute lymphoid leukemia play a decisive role on the therapeutical effect of anti-neoplastic drugs. The presence and activity of these enzymatic complexes are genetically coded and subjected to allele variations, the frequency of which is variable in the different human populations. This genetic polymorphism has an impact on the therapeutic effectiveness of drugs and determines the lack or the existence of toxicity that may sometimes become lethal. The enzymes called thiopurine-methyltransferase, methylen-tetrahydropholate-reductase and glutathione-transferase are detoxifying systems of some of the chemotherapeutic drugs that are used for the treatment of acute lymphoid leukemia. This paper reviewed the genetic characteristics of the enzymes, the frequency of polymorphisms and the clinical implications of their expression. Similarly, the importance and the benefits of genotyping before the treatment were discussed in order to change the drug doses to maximize the therapeutic effect and reduce toxicity. Pharmacogenetics has experienced great development in the last few years and draws growing interest; the knowledge about and the implementation of this discipline will take us to the customized medicine

MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy

The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression

CYP2C19⁎2 Polymorphism in Chilean Patients with In-Stent Restenosis Development and Controls

Clopidogrel is an antiplatelet drug especially used in patients undergoing percutaneous coronary interventions (PCI). Polymorphisms within CYP2C19 can result in important interindividual variations regarding therapeutic efficacy. Therefore, we aimed to evaluate the impact of the CYP2C19⁎2 variant (rs4244285) on in-stent restenosis occurrence in Chilean patients who underwent PCI and received clopidogrel. A total of 77 cases with stenosis >50% in the angioplasty site (62.75 ± 9.8 years, 80.5% males) and 86 controls (65.45 ± 9.8 years, 72.1% males) were studied. The polymorphism was genotyped using TaqMan® Drug Metabolism Genotyping Assays. Overall, CYP2C19⁎2 allele frequency was 8.3%. Diabetes, chronic lesions, and bare metal stents (BMS) were observed more often in cases than in controls (p = 0.05, p = 0.04, and p = 0.02, resp.). Genotypic frequencies did not differ significantly between the groups (p = 0.15). Nonetheless, the mutated allele was observed in a greater proportion in patients without in-stent restenosis (p = 0.055). There was no significant association between the rs4244285 variant and the occurrence of in-stent restenosis after PCI (OR = 0.44; 95% CI: 0.19 to 1.04; p = 0.06). In summary, no association was identified between the CYP2C19⁎2 variant and the development of coronary in-stent restenosis