The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics

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dc.contributor.authorBizerra, Paulo Francisco Veiga
dc.contributor.authorItou da Silva, Fernanda Sayuri
dc.contributor.authorGilglioni, Eduardo Hideo
dc.contributor.authorNanami, Letícia Fernanda
dc.contributor.authorKlosowski, Eduardo Makiyama
dc.contributor.authorde Souza, Byanca Thais Lima
dc.contributor.authorRaimundo, Ana Flávia Gatto
dc.contributor.authordos Santos, Karina Borba Paulino
dc.contributor.authorMewes, Juliana Moraes
dc.contributor.authorConstantin, Renato Polimeni
dc.contributor.authorMito, Márcio Shigueaki
dc.contributor.authorIshii-Iwamoto, Emy Luiza
dc.contributor.authorConstantin, Jorgete
dc.contributor.authorMingatto, Fábio Ermínio [UNESP]
dc.contributor.authorEsquissato, Giovana Natiele Machado
dc.contributor.authorMarchiosi, Rogério
dc.contributor.authordos Santos, Wanderley Dantas
dc.contributor.authorFerrarese-Filho, Osvaldo
dc.contributor.authorConstantin, Rodrigo Polimeni
dc.contributor.institutionState University of Maringá
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2023-07-29T16:15:36Z
dc.date.available2023-07-29T16:15:36Z
dc.date.issued2023-07-01
dc.description.abstractClomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 μM to 59.64 μM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes.en
dc.description.affiliationDepartment of Biochemistry Laboratory of Biological Oxidations State University of Maringá, Paraná
dc.description.affiliationDepartment of Biochemistry Laboratory of Plant Biochemistry State University of Maringá, Paraná
dc.description.affiliationLaboratory of Metabolic and Toxicological Biochemistry São Paulo State University, São Paulo
dc.description.affiliationUnespLaboratory of Metabolic and Toxicological Biochemistry São Paulo State University, São Paulo
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFisheries Agency,Council of Agriculture
dc.format.extent1-16
dc.identifierhttp://dx.doi.org/10.1016/j.toxlet.2023.05.008
dc.identifier.citationToxicology Letters, v. 383, p. 1-16.
dc.identifier.doi10.1016/j.toxlet.2023.05.008
dc.identifier.issn1879-3169
dc.identifier.issn0378-4274
dc.identifier.scopus2-s2.0-85160766821
dc.identifier.urihttp://hdl.handle.net/11449/250022
dc.language.isoeng
dc.relation.ispartofToxicology Letters
dc.sourceScopus
dc.subjectCellular structure
dc.subjectIntact liver
dc.subjectIsolated hepatocytes
dc.subjectIsolated mitochondria
dc.subjectMitochondrial toxicity
dc.subjectTricyclic antidepressants
dc.titleThe harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergeticsen
dc.typeArtigo
unesp.departmentZootecnia - FCATpt

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Dracena - FCAT - Faculdade de Ciências Agrárias e Tecnológicas