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

被引:8
作者
de Moura, Soraia Santana [1 ]
de Avila, Renato Ivan [1 ]
Brito, Lara Barroso [1 ]
de Oliveira, Rhaul [2 ,3 ]
Rodrigues de Oliveira, Gisele Augusto [1 ]
Pazini, Francine [4 ]
Menegatti, Ricardo [4 ]
Batista, Aline Carvalho [5 ]
Grisolia, Cesar Koppe [2 ]
Valadares, Marize Campos [1 ]
机构
[1] Univ Fed Goias, Fac Farm, FarmaTec, Lab Farmacol & Toxicol Celular, Goiania, Go, Brazil
[2] Univ Brasilia, Inst Biol, Lab Genet Toxicol GeTOX, Brasilia, DF, Brazil
[3] Univ Estadual Campinas, Fac Technol, Lab Ecotoxicol & Microbiol Ambiental Prof Dr Abil, Sao Paulo, Brazil
[4] Univ Fed Goias, Fac Farm, LQFM, Goiania, Go, Brazil
[5] Univ Fed Goias, Fac Odontol, Dept Estomatol Patol Oral, Goiania, Go, Brazil
关键词
Pyrazole; Molecular hybridization; Zebrafish; Subchronic toxicity; Genotoxicity; Anti-inflammatory drugs; UNITED-STATES; DERIVATIVES; ZEBRAFISH; TOXICITY; DOCKING; DESIGN; AGENTS;
D O I
10.1016/j.cbi.2017.09.004
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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/KATP 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 N-o 487/2014). Moreover, zebrafish model was used to assess the embryotoxicity potential of LQFM021 using fish embryo toxicity test (OECD N-o 236/2013) with extended exposure to evaluate subchronic larval development. In vivo subchronic toxicity of LQFM021 in rats (OECD N-o 407/2008) was also conducted. This compound at the lower concentrations tested (3.1 and 31 mu g/mL) did not promote changes in micronuclei frequency in HepG2 cells. However, in the higher concentrations of LQFM021 (310 and 620 mu g/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 mu g/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 mu g/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). (C) 2017 Elsevier B.V. All rights reserved.
引用
收藏
页码:185 / 194
页数:10
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