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

• Published in: Toxicology reports Vol. 7; pp. 217 - 232
• Main Authors: de Sá Hyacienth, Beatriz Martins, Tavares Picanço, Karyny Roberta, Sánchez-Ortiz, Brenda Lorena, Barros Silva, Luciane, Matias Pereira, Arlindo César, Machado Góes, Larissa Daniele, Sousa Borges, Raphaelle, Cardoso Ataíde, Rodrigo, dos Santos, Cleydson Breno Rodrigues, de Oliveira Carvalho, Helison, Gonzalez Anduaga, Gloria Melisa, Navarrete, Andrés, Tavares Carvalho, José Carlos
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.01.2020; Elsevier
• Subjects: Bergenin; Biotrasformation; Endopleura uchi; Hepatoxity; Nephrotoxity; Regular; Toxicology; MM; Bergenin; HIA; AST; hERG; BBB; P-Gp; PPB; HBA; Biotrasformation; ALT; HBD; HAI; Hepatoxity; Toxicology; EEu; Nephrotoxity; IAN; Endopleura uchi; HBD, Hydrogen bonding donors; BBB, Brain-blood partition coefficient (C.brain/C.blood); hERG, ether-a-go-related human gene; P-Gp, P-glycoprotein; HIA, Human intestinal absorption; MM, Molecular mass; HBA, Hydrogen bonding acceptors; IAN, Regional Herbarium of the Eastern Amazonian Embrapa; ALT, Alanine aminotransferase; HAI, Index of Histopathological Changes; PPB, Plasma protein binding; AST, Aspartate aminotransferase; EEu, Endopleura uchi stem bark hydroethanolic extract
• ISSN: 2214-7500; 2214-7500
• DOI: 10.1016/j.toxrep.2020.01.011

[Display omitted] •E. uchi stem bark hydroethanolic extract in zebrafish.•Evaluating the in silico pharmacokinetic and toxicological parameters.•Behavioral, biochemical and histopathological changes was dose dependent.•In silico bergenin and its metabolites showed high intestinal absorption.•Bergenin inhibited CYP2C9, CYP3A4 and CYP2C19. 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.