(4) THE MITOCHONDRIAL PERMEABILITY TRANSITION DURING CHRONIC FEEDING WITH THE HEPATOCARCINOGEN 2-ACETYLAMINOFLUORENE

P-C. Klöhn^1,3*, M.E. Soriano¹, W. Irwin¹, A. Bitsch², H-G. Neumann² and P. Bernardi^1
1Department of Biomedical Sciences, University of Padova, Italy
²Department of Toxicology, Universität Würzburg, Germany
³Current address:  Institute of Toxicology and Genetics, Forschungszentrum Karlsruhe, Germany

The in vivo regulation of the mitochondrial permeability transition pore (PTP), which is supposed to play an important role in apoptosis, is not well understood. Liver mitochondria from rats fed a diet containing the hepatocarcinogen 2-acetylaminofluorene (AAF) are resistant to the permeability transition (PT) induced by the toxic AAF metabolite, 2-nitrosofluorene (NOF) [1].  We have investigated the mechanism by which NOF induces the PT in isolated mitochondria, and studied whether PTP adaptive changes can be demonstrated in primary cultures of hepatocytes from AAF-fed animals. We found that NOF opens the PTP at the P-site (which is in apparent redox equilibrium with the pyridine nucleotides pool), and that adaptation involves increased expression of cytochrome c oxidase.  Hepatocytes from AAF-fed rats were resistant to PTP opening, and this mitochondrial adaptive change occurred as early as after 2 weeks of AAF feeding. These results indicate that mitochondrial adaptation is the earliest detectable change in the course of AAF-feeding, and suggest that increased resistance to PTP opening may be a causative event in the expansion of mutated cells that become resistant to apoptosis.

[1]  Klöhn, P.-C. et al. (1998) Carcinogenesis 19:1185-1190

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