Mitochondrial and liver oxidative stress alterations induced by N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine: relevance for hepatotoxicity

Journal of Applied Toxicology - Tập 33 Số 6 - Trang 434-443 - 2013
Maria Manuel Oliveira1, José Teixeira2, Cármen Nóbrega3, Luís Félix2, Vilma A. Sardão4, Aura Colaço5, Paula A. Oliveira5, Francisco Peixoto2
1Chemistry Department, CQVR University of Trás‐os‐Montes and Alto Douro 5001‐801 Vila Real Portugal
2Chemistry Department, CECAV University of Trás‐os‐Montes and Alto Douro 5001‐801 Vila Real Portugal
3Agrarian School of Viseu Polytechnic Institute of Viseu 3500‐606 Viseu Portugal
4Centre for Neuroscience and Cell Biology 3004‐517 Coimbra Portugal
5Department of Veterinary Sciences, CECAV University of Trás‐os‐Montes and Alto Douro 5001‐801 Vila Real Portugal

Tóm tắt

ABSTRACTThe most significant toxicological effect of nitrosamines like N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) is their carcinogenic activity, which may result from exposure to a single large dose or from chronic exposure to relatively small doses. However, its effects on mitochondrial liver bioenergetics were never investigated. Liver is the principal organ responsible for BBN metabolic activation, and mitochondria have a central function in cellular energy production, participating in multiple metabolic pathways. Therefore any negative effect on mitochondrial function may affect cell viability. In the present work, ICR male mice were given 0.05% of BBN in drinking water for a period of 12 weeks and were sacrificed one week later. Mitochondrial physiology was characterized in BBN‐ and control‐treated mice. Transmembrane electric potential developed by mitochondria was significantly affected when pyruvate–malate was used, with an increase in state 4 respiration observed for pyruvate–malate (46%) and succinate (38%). A decrease in the contents of one subunit of mitochondrial complex I and in one subunit of mitochondrial complex IV was also observed. In addition, the activity of both complexes I and II was also decreased by BBN treatment. The treatment with BBN increases the susceptibility of liver mitochondria to the opening of the mitochondrial permeability transition pore. This susceptibility could be related with the increase in the production of H2O2 by mitochondria and increased oxidative stress confirmed by augmented susceptibility to lipid peroxidation. These results lead to the conclusion that hepatic mitochondria are one primary target for BBN toxic action during liver metabolism. Copyright © 2011 John Wiley & Sons, Ltd.

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Journal of Applied Toxicology

Tập 33 Số 6

434-443

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