当前位置： SCI文献检索 > LIFE SCIENCES期刊下所有文献 > Effects of all-trans-retinoic acid on the permeability transition and bioenergetic functions of rat liver mitochondria in combination with endoxifen.

Effects of all-trans-retinoic acid on the permeability transition and bioenergetic functions of rat liver mitochondria in combination with endoxifen.

Abstract：

AIMS:The clinical utilization of the combinations of all-trans-retinoic acid (RA) with antiestrogens, which present synergism of action in breast cancer, has been limited by RA adverse effects, including hepatotoxicity, which may be related with mitochondrial damage. This work evaluated the effects of RA alone and in combination with the antiestrogen endoxifen (EDX) on liver mitochondria. MAIN METHODS:Mitochondrial permeability transition (MPT) was assessed by using Calcium Green-5N fluorescence and a tetraphenylphosphonium selective electrode. Oxidative stress was evaluated by oxygen consumption and thiobarbituric acid method. Mitochondrial bioenergetic was monitored by measuring oxygen consumption and mitochondrial membrane potential (ΔΨ). Osmotic volume changes of mitochondria were followed at 540nm. KEY FINDINGS:EDX prevents the MPT induced by RA, allowing mitochondria pre-incubated with RA to accumulate Ca(2+) and inhibiting the depolarization of ΔΨ. RA above 10 nmol/mg protein depresses the phosphorylation capacity of mitochondria, as shown by the increase in the time required for ADP phosphorylation as well as by the decrease in state 3 respiration. At 20 nmol/mg protein, RA decreases the ΔΨ and increases the state 4 respiration, suggesting that high concentrations of RA permeabilize the membrane to protons, possibly due to a proton leak through the Fo fraction of complex V. Moreover, the effects of RA on mitochondrial bioenergetics are not changed by EDX. SIGNIFICANCE:RA-induced hepatotoxicity may be related with induction of MPT and alterations in bioenergetic parameters; the combination with EDX, which reduces mitochondrial dysfunction and synergistically potentiates the anticancer activity, may provide a safer therapeutic strategy.

journal_name

Life Sci

journal_title

Life sciences

authors

Ribeiro MP,Santos AE,Santos MS,Custódio JB

doi

10.1016/j.lfs.2013.05.027

subject

Has Abstract

pub_date

2013-07-30 00:00:00

pages

96-107

issue

2-3

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(13)00316-0

journal_volume

pub_type

杂志文章

在线工具

Effects of all-trans-retinoic acid on the permeability transition and bioenergetic functions of rat liver mitochondria in combination with endoxifen.