Toxicology Reports (Jan 2020)

Hydroethanolic extract from Endopleura uchi (Huber) Cuatrecasas and its marker bergenin: Toxicological and pharmacokinetic studies in silico and in vivo on zebrafish

  • Beatriz Martins de Sá Hyacienth,
  • Karyny Roberta Tavares Picanço,
  • Brenda Lorena Sánchez-Ortiz,
  • Luciane Barros Silva,
  • Arlindo César Matias Pereira,
  • Larissa Daniele Machado Góes,
  • Raphaelle Sousa Borges,
  • Rodrigo Cardoso Ataíde,
  • Cleydson Breno Rodrigues dos Santos,
  • Helison de Oliveira Carvalho,
  • Gloria Melisa Gonzalez Anduaga,
  • Andrés Navarrete,
  • José Carlos Tavares Carvalho

Journal volume & issue
Vol. 7
pp. 217 – 232

Abstract

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Endopleura uchi, is used for the treatment of inflammatory disease and related to the female reproductive tract. The aim of this study was to evaluate the acute toxicity of the Endopleura uchi stem bark hydroethanolic extract (EEu) in zebrafish, emphasizing the histopathological and biochemical parameters, as well as evaluating the in silico pharmacokinetic and toxicological parameters of the phytochemical/pharmacological marker, bergenin, as their metabolites. The animals were orally treated with EEu at a single dose of 75 mg/kg, 500 mg/kg, 1000 mg/kg and 3000 mg/kg. the oral LD50 of the EEu higher to the dose of 3000 mg/kg. Behavioral, biochemical and histopathological changes were dose dependent. In silico pharmacokinetic predictions for bergenin and its metabolites showed moderate absorption in high human intestinal absorption (HIA) and Caco-2 models, reduced plasma protein binding, by low brain tissue binding and no P-glycoprotein (P-Gp) inhibition. Their metabolism is defined by the CYP450 enzyme, in addition to bergenin inhibition of CYP2C9, CYP3A4 and CYP2C19. In the bergenin and its metabolites in silico toxicity test it have been shown to cause carcinogenicity and a greater involvement of the bergenin with the CYP enzymes in the I and II hepatic and renal metabolism’s phases was observed. It is possible to suggest that the histopathological damages are involved with the interaction of this major compound and its metabolites at the level of the cellular-biochemical mechanisms which involve the absorption, metabolization and excretion of these possible prodrug and drug.

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