4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

Cardoso, Carla M. P.; Almeida, Leonor M.; Custódio, José B.A.

doi:10.1016/s1567-7249(02)00034-x

Cited by 21 publications

(17 citation statements)

References 49 publications

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“…Simpson et al [54] observed that TAM exerted a CsA-like action on SH-SY5Y neuroblastoma mitochondria. Similarly, Cardoso et al [26] observed that 20 mM OHTAM caused a total inhibition of Ca 2þ -induced depolarization of succinate-energized liver mitochondria similar to that exerted by CsA. As discussed previously, due to tissue-specific differences in mitochondria pore properties [37], the ability of both agents, OHTAM and CsA, to protect against MPTP induction differs significantly between different types of mitochondria.…”

Section: Discussionmentioning

confidence: 55%

“…Since previous studies [26] demonstrated the inhibitory effect of OHTAM on MPTP induction, we tested the effect of OHTAM on Ca 2þ -induced MPTP of isolated brain mitochondria. MPTP causes a non-selective permeabilization of the inner mitochondrial membrane typically promoted by the accumulation of excessive quantities of Ca 2þ ions and stimulated by a variety of compounds or conditions [24].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicate that TAM [25] and OHTAM [26] are potent inhibitors of the MPTP in liver mitochondria. Furthermore, Hoyt et al [27] reported that TAM could be an inhibitor of the MPTP in intact neurons.…”

Section: Introductionmentioning

confidence: 98%

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Hydroxytamoxifen protects against oxidative stress in brain mitochondria

Moreira

Custódio

Oliveira

et al. 2004

Biochemical Pharmacology

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This study evaluated the effect of hydroxytamoxifen, the major active metabolite of tamoxifen (synthetic, nonsteroidal antiestrogen drug), on the function of brain mitochondria. We observed that only high concentrations of hydroxytamoxifen (60 nmol/mg protein) induced a significant decrease in RCR, while ADP/O ratio remained statistically unchanged. Similarly, only the highest concentration of hydroxytamoxifen (60 nmol/mg protein) affected the phosphorylative capacity of brain mitochondria, characterized by a decrease in the repolarization level and an increase in the repolarization lag phase. We observed that all the concentrations of hydroxytamoxifen tested (7.5, 15 and 30 nmol/mg protein) prevented lipid peroxidation induced by the oxidant pair ADP/Fe 2þ . Furthermore, through the analyses of calcium fluxes and mitochondrial transmembrane potential parameters, we observed that hydroxytamoxifen (30 nmol/mg protein) exerted some protection against pore opening, although in a less extension than that promoted by cyclosporin A, the specific inhibitor of the mitochondrial permeability transition pore. However, in the presence of hydroxytamoxifen plus cyclosporin A, the protection observed was significantly higher when compared with that induced by both agents alone.These results support the idea that hydroxytamoxifen protects lipid peroxidation and inhibits the mitochondrial permeability transition pore in brain. Since numerous neurodegenerative diseases are intimately related with mitochondrial dysfunction resulting from lipid peroxidation and induction of mitochondrial permeability transition, among other factors, future therapeutical strategies could be designed taking in account this neuroprotective role of hydroxytamoxifen, which is pharmacologically much more potent and less toxic than its promoter tamoxifen. #

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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Hydroxytamoxifen protects against oxidative stress in brain mitochondria

Moreira

Custódio

Oliveira

et al. 2004

Biochemical Pharmacology

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“…2 and 3). Accordingly, previous in vitro studies also indicate that TAM (Custodio et al, 1998;Moreira et al, 2005) and OHTAM (Cardoso et al, 2002;Moreira et al, 2004) are potent inhibitors of PTP induction in liver and brain mitochondria. However, we observed that E2 exposure does not interfere with Ca 2+ influx (Fig.…”

Section: Discussionmentioning

confidence: 77%

Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

Moreira

Custódio

Nunes

et al. 2007

Toxicology and Applied Pharmacology

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Given the tremendous importance of mitochondria to basic cellular functions as well as the critical role of mitochondrial impairment in a vast number of disorders, a compelling question is whether 17β-estradiol (E2) modulates mitochondrial function. To answer this question we exposed isolated liver mitochondria to E2. Three groups of rat females were used: control, ovariectomized and ovariectomized treated with tamoxifen. Tamoxifen has antiestrogenic effects in the breast tissue and is the standard endocrine treatment for women with breast cancer. However, under certain circumstances and in certain tissues, tamoxifen can also exert estrogenic agonist properties. We observed that at basal conditions, ovariectomy and tamoxifen treatment do not induce any statistical alteration in oxidative phosphorylation system and respiratory chain parameters. Furthermore, tamoxifen treatment increases the capacity of mitochondria to accumulate Ca 2+ delaying the opening of the permeability transition pore. The presence of 25 μM E2 impairs respiration and oxidative phosphorylation system these effects being similar in all groups of animals studied. Curiously, E2 protects against lipid peroxidation and increases the production of H 2 O 2 in energized mitochondria of control females. Our results indicate that E2 has in general deleterious effects that lead to mitochondrial impairment. Since mitochondrial dysfunction is a triggering event of cell degeneration and death, the use of exogenous E2 must be carefully considered.

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“…TAM and OHTAM are potent inhibitors of MPT pore opening probably due to its antioxidants properties (Custodio et al 1998;Cardoso et al 2002b). Therefore, to clarify the biochemical mechanisms by which MPT pore opening is potentiated by isotretinoin, we evaluated the effects of thiol protecting and antioxidants agents that prevent the MPT pore opening induced by oxidative stress mechanisms.…”

Section: Effect Of Antiestrogenic Compounds On Mpt Pore Opening Inducmentioning

confidence: 99%

The antiestrogen 4-hydroxytamoxifen protects against isotretinoin-induced permeability transition and bioenergetic dysfunction of liver mitochondria: comparison with tamoxifen

Silva

Ribeiro

Santos

et al. 2013

J Bioenerg Biomembr

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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 Ca 2+ -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 Ca 2+ 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 Ca 2+ -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.

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4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

Cited by 21 publications

References 49 publications

Hydroxytamoxifen protects against oxidative stress in brain mitochondria

Hydroxytamoxifen protects against oxidative stress in brain mitochondria

Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats

The antiestrogen 4-hydroxytamoxifen protects against isotretinoin-induced permeability transition and bioenergetic dysfunction of liver mitochondria: comparison with tamoxifen

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