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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Cytotoxicity of monocrotaline in isolated rat hepatocytes: Effects of dithiothreitol and fructose

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Author(s):
Maioli, Marcos A. [1] ; Alves, Larissa C. [1] ; Perandin, Diego [1] ; Garcia, Andrea F. [1] ; Pereira, Flavia T. V. [2] ; Mingatto, Fabio E. [1]
Total Authors: 6
Affiliation:
[1] Univ Estadual Paulista, UNESP, Lab Bioquim Metab & Toxicol, BR-17900000 Dracena, SP - Brazil
[2] Univ Estadual Paulista, UNESP, Lab Morfofisiol Placenta & Embriao, BR-17900000 Dracena, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Toxicon; v. 57, n. 7-8, p. 1057-1064, JUN 2011.
Web of Science Citations: 10
Abstract

Monocrotaline (MCT) is a pyrrolizidine alkaloid present in plants of the Crotalaria species that causes cytotoxicity and genotoxicity, including hepatotoxicity in animals and humans. It is metabolized by cytochrome P-450 in the liver to the alkylating agent dehydromonocrotaline (DHM). In previous studies using isolated rat liver mitochondria, we observed that DHM, but not MCT, inhibited the activity of respiratory chain complex I and stimulated the mitochondrial permeability transition with the consequent release of cytochrome c. In this study, we evaluated the effects of MCT and DHM on isolated rat hepatocytes. DHM, but not MCT, caused inhibition of the NADH-linked mitochondrial respiration. When hepatocytes of rats pre-treated with dexamethasone were incubated with MCT (5 mM), they showed ALT leakage, impaired ATP production and decreased levels of intracellular reduced glutathione and protein thiols. In addition, MCT caused cellular death by apoptosis. The addition of fructose or dithiotreitol to the isolated rat hepatocyte suspension containing MCT prevented the ATP depletion and/or glutathione or thiol oxidation and decreased the ALT leakage and apoptosis. These results suggest that the toxic effect of MCT on hepatocytes may be caused by metabolite-induced mitochondrial energetic impairment, together with a decrease of cellular glutathione and protein thiols. (C) 2011 Elsevier Ltd. All rights reserved. (AU)