Carcinogenesis, Vol 19, 1185-1190, Copyright © 1998 by Oxford University Press
PC Klohn, A Bitsch and HG Neumann
The tumour promoting properties of carcinogenic 2-acetylaminofluorene (AAF)
in rat liver are essentially unknown. We proposed that mitochondria are a
target for the cytotoxic effects of 2- nitrosofluorene (NOF), a metabolite
of AAF, since NOF induces a redox- cycle at complex I and complex III of
the respiratory chain, and impairs respiration and oxidative
phosphorylation. We now demonstrate that NOF is a potent inducer of the
mitochondrial permeability transition pore (PTP) in isolated mitochondria.
In the presence of Ca2+, NOF induced rapid swelling of mitochondria in a
dose-dependent manner and depolarized the mitochondrial membrane.
Permeability transition as well as depolarization were abolished completely
by pre- incubation with the PTP inhibitor cyclosporin A. To study whether
the PTP is involved in in vivo toxicity, rats were fed a diet containing
AAF (0.04%) for 2 weeks. After isolation of mitochondria, permeability
transition was induced by high Ca2+ concentrations (150-400 microM) or
phosphate plus Ca2+. Swelling was determined as maximal rate of absorption
decrease at 540 nm (delta A/delta t). Surprisingly, delta A/delta t-values
of mitochondria from AAF-fed rats were significantly lower (16.3 +/- 4.8 x
10(3)/min) than of mitochondria from control animals (32.7 +/- 4.1 x
10(3)/min; P < 0.02). In the presence of phosphate (15 mM), delta
A/delta t-values of mitochondria from AAF-fed rats were even lower (10% of
control). Moreover, the membrane potential which was dissipated rapidly by
the PTP-inducer NOF (30 microM) at a Ca2+ concentration of 80 microM in
mitochondria from control animals, remained constant in mitochondria of
AAF-treated rats. We therefore propose that the regulation of the PTP is
altered on chronic AAF- feeding. The increased resistance of mitochondria
against permeability transition may alter the threshold for apoptosis and
thus suppress apoptosis. We also discuss the role of epigenetic
modifications in early stages of carcinogenesis.
ARTICLES
Mitochondrial permeability transition is altered in early stages of carcinogenesis of 2-acetylaminofluorene
Department of Toxicology, University of Wurzburg, Germany.
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