Author(s):
Silva, Filomena S. G. 
; Ribeiro, Mariana P. C. ; Santos, M. S. ; Rocha-Pereira, Petronila ; Santos-Silva, Alice ; Custódio, José B. A.
Date: 2013
Persistent ID: http://hdl.handle.net/10316/25792
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Isotretinoin; 4-hydroxytamoxifen; Tamoxifen; Oxidative phosphorylation system; Mitochondrial permeability transition
Description
The combination of isotretinoin (13-cis-retinoic
acid) with antiestrogens seems to be a promising strategy
for cancer chemotherapy. The aim of the study was to
evaluate the effects of isotretinoin alone or in combination
with 4-hydroxytamoxifen (OHTAM) and with its
prodrug tamoxifen (TAM), on the functions of rat liver mitochondria, i.e., mitochondrial permeability transition
(MPT), bioenergetic functions and adenine nucleotide
translocase (ANT). Isotretinoin (5 nmol/mg protein) induced
the Ca2+-dependent MPT pore opening in mitochondria
energized with succinate, which was prevented
by OHTAM, cyclosporine A, TAM and ANT ligands.
When mitochondria were energized with glutamate/malate
and in the absence of added Ca2+ isotretinoin decreased
the state 3 respiration, the ATP levels, the active ANT
content and increased the lag phase of the phosphorylation
cycle, demonstrating that isotretinoin decreased the
mitochondrial phosphorylation efficiency. These changes
of isotretinoin in bioenergetic parameters were not significant
in the presence of succinate. The effects of isotretinoin
at 5 nmol/mg protein on the Ca2+-dependent MPT
and phosphorylative efficacy may be related with interactions
with the ANT. Above 10 nmol/mg protein isotretinoin
strongly diminished the active ANT content,
decreased the Δψ, inhibited the complex I and induced
proton leak through the Fo fraction of complex V. The
combination of OHTAM with isotretinoin only induced significant
changes in the energy production systems at concentrations
≥5 nmol isotretinoin/mg protein. Therefore, our results
suggest that isotretinoin-associated liver toxicity is possibly
related with mitochondrial dysfunctions and that the combination
with OHTAM may contribute to decrease its toxicity. This study was supported by PhD grant (SFRH/
BD/37686/2007) attributed to F.S.G. Silva by Fundação para a Ciência
e Tecnologia.
