Investigação da atividade toxicológica de análogos de estatinas em modelos experimentais in vitro

Abstract

Statin drugs are competitive inhibitors of the enzyme 3-hydroxy-methyl-glutaryl coenzyme A (HMGCoA) reductase, widely used for the control of hypercholesterolemia and overall, in particular for the reduction of serum LDLc (Low Density Lipoprotein cholesterol). In addition to the primary effect, these drugs have many secondary effects, called pleiotropic effects, involving anti-inflammatory, antitumor, and antiparasitic activities. For the development of innovations in the field of medicinal chemistry is essential to evaluate the risk of adverse health effects, or in other words, the therapeutic safety of the new product under the proposed conditions of use. Accordingly, the aim of this study was to investigate the genotoxicity of four analogues of lipid biosynthesis inhibitors, from the class of statins in experimental models in vitro, previously tested against the W2 clone of Plasmodium falciparum to obtain the IC50 of these molecules against the pathogen. Four new molecules (PCSR02.001, PCSR09.001, PCSR08.002 and PCSR10.002) were developed. For the assessment of toxicity, bacterial mutagenicity test (Ames test) were performed, the cell viability assay using WST-1 reagent and micronuclei induction assay, both using an ovarian lineage (CHO-K1) and an hepatic lineage (HepG2). Taking into account the fact that none of the samples have induced mutagenic effects in strains of S. enterica serovar Typhimurium , and PCSR10.002 have shown cytotoxicity then we suggest that this compound is the most toxic. Comparatively, PCSR10.002 was more cytotoxic and genotoxic for the CHO-K1 cell line, than for HepG2 line. PCSR02.001 showed high genotoxic potential for ovarian cells, but was not able to induce the formation of micronuclei in liver cells, thus showing a similar profile to that observed in PCSR10.002. Just like atorvastatin, PCSR09.001 showed high pro-apoptotic potential for hepatocyte lineage. Have PCSR08.002, showed an increase in apoptosis of CHO-K1. The induction of apoptosis is not necessarily an adverse event, since little is harmful and responsible for the elimination of damaged cells. However, the apoptotic responses induced by this compound were much lower than those induced by atorvastatin (about 4 times less than atorvastatin). PCSR08.002 was that was less toxic and this sample had a lower relative risk in a global analysis of the responses and cytotoxicity demonstrated no genotoxic potential for strains used in this study. Therefore it is concluded that the analysis of toxicological activity using in vitro experimental models of these statins is an important step towards the establishment of more safely new candidate-drugs.