Toxicological Sciences, Vol 48, 82-89, Copyright © 1999 by Society of Toxicology
S Zhou and KB Wallace
Peroxisome proliferators are a group of structurally diverse chemicals that
cause the proliferation of peroxisomes in rodents. The purpose of this
investigation was to test the hypothesis that the shared effect of these
compounds on peroxisome proliferation is mediated through a common
inhibitory effect on mitochondrial bioenergetics. Freshly isolated rat
liver mitochondria were energized with succinate. The effect of the
chemicals on mitochondrial bioenergetics was analyzed by monitoring
calcium-induced changes in membrane potential and swelling, as well as
changes in mitochondrial respiration. Mitochondrial membrane potential was
measured with a TPP(+)-sensitive electrode, and swelling was recorded
spectrophotometrically. Mitochondrial oxygen uptake was monitored with a
Clark-type oxygen electrode. Gemfibrozil and WY-14,643 induced the
mitochondrial permeability transition as characterized by calcium-induced
swelling and depolarization of membrane potential, both of which were
inhibited by cyclosporine A. Fenofibrate, clofibrate, ciprofibrate and
diethylhexyl phthalate, on the other hand, caused a direct dose-dependent
depolarization of mitochondrial membrane potential. However, the mechanism
of membrane depolarization varied among the test chemicals. Bezafibrate and
trichloroethylene elicited no effect on succinate-supported mitochondrial
bioenergetics. The results of this investigation demonstrate that although
most, but not all, peroxisome proliferators interfere with mitochondrial
bioenergetics, the specific biomolecular mechanism differs among the
individual compounds.
ARTICLES
The effect of peroxisome proliferators on mitochondrial bioenergetics
Department of Biochemistry and Molecular Biology, University of Minnesota School of Medicine, Duluth 55812, USA.
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