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

doi:10.1016/j.toxrep.2020.01.011

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

Toxicol Rep. 2020 Jan 27:7:217-232. doi: 10.1016/j.toxrep.2020.01.011. eCollection 2020.

Authors

Beatriz Martins de Sá Hyacienth^{1

2}, Karyny Roberta Tavares Picanço¹, Brenda Lorena Sánchez-Ortiz^{1

3}, Luciane Barros Silva⁴, Arlindo César Matias Pereira¹, Larissa Daniele Machado Góes¹, Raphaelle Sousa Borges¹, Rodrigo Cardoso Ataíde¹, Cleydson Breno Rodrigues Dos Santos^{1

4}, Helison de Oliveira Carvalho¹, Gloria Melisa Gonzalez Anduaga³, Andrés Navarrete³, José Carlos Tavares Carvalho^{1

2}

Affiliations

¹ Laboratory of Pharmaceutical Research, Department of Biological Sciences and Health, Federal University of Amapá, Juscelino Kubitschek Street, Marco Zero Campus, Zip Code 68903-419, Macapá, AP, Brazil.
² Postgraduate Program in Biodiversity and Biotechnology of the Legal Amazon of the BIONORTE Network, Department of Biological Sciences and Health, Federal University of Amapá, Macapá, AP, Brazil.
³ Laboratory of Natural Product Pharmacology, Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico, University City, Coyoacán, Zip Code 04510 Mexico City, Mexico.
⁴ Federal University of Amapá, Laboratory of Modeling and Computational Chemistry, Department of Biological Sciences and Health, Juscelino Kubitschek Street, Marco Zero Campus, Zip Code 68903-419, Macapá, AP, Brazil.

Abstract

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.

Keywords: ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; BBB, Brain-blood partition coefficient (C.brain/C.blood); Bergenin; Biotrasformation; EEu, Endopleura uchi stem bark hydroethanolic extract; Endopleura uchi; HAI, Index of Histopathological Changes; HBA, Hydrogen bonding acceptors; HBD, Hydrogen bonding donors; HIA, Human intestinal absorption; Hepatoxity; IAN, Regional Herbarium of the Eastern Amazonian Embrapa; MM, Molecular mass; Nephrotoxity; P-Gp, P-glycoprotein; PPB, Plasma protein binding; Toxicology; hERG, ether-a-go-related human gene.