In?vitro genotoxicity and in?vivo subchronic evaluation of the anti-inflammatory pyrazole compound LQFM021

摘要

Abstract Scientific evidences have highlighted 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM021) as a promising anti-inflammatory, analgesic and antinociceptive agent due to its effects on peripheral opioid receptors associated with activation of the nitric oxide/cGMP/K ATP pathway. Despite these important pharmacological findings, toxicity data of LQFM021 are scarce. Thus, this study investigated the in?vitro genotoxicity of LQFM021 through cytokinesis-block micronucleus assay (OECD No 487/2014). Moreover, zebrafish model was used to assess the embryotoxicity potential of LQFM021 using fish embryo toxicity test (OECD No 236/2013) with extended exposure to evaluate subchronic larval development. In?vivo subchronic toxicity of LQFM021 in rats (OECD No 407/2008) was also conducted. This compound at the lower concentrations tested (3.1 and 31?μg/mL) did not promote changes in micronuclei frequency in HepG2 cells. However, in the higher concentrations of LQFM021 (310 and 620?μg/mL) triggered a significant increase of micronucleated HepG2 cells, showing an alert signal of potential genotoxicity. Regarding the oral treatment of rats with LQFM021 (62.5, 125 or 250?mg/kg) for 28 days, the main findings showed that LQFM021 promoted renal and liver changes in a dose-dependent manner, being irreversible damage for kidneys while liver tissue showed a recovery after 14 days post treatment. Regarding embryotoxicity, although the lower concentrations used did not show toxicity, the concentration of LQFM021 (39.8 and 100?mg/L) promoted malformations in zebrafish embryo-larvae stage, in especial cardiac tissue changes. In conclusion, anti-inflammatory compound LQFM021 seems to have some limiting factors as a new therapeutic option to be used orally and in high repeated doses, related to those found in the non-steroidal anti-inflammatory drugs (NSAIDs). Highlights ? Pyrazole LQFM021 was able to promote increase of micronucleated HepG2 cells. ? LQFM021 promoted irreversible renal and reversible liver changes in rats. ? Lower LQFM021 concentrations did not show potential embryotoxicity in zebrafish. ? Higher LQFM021 concentrations promoted malformations in embryo-larvae zebrafish.