title: The antiestrogen endoxifen protects rat liver mitochondria from permeability transition pore opening and oxidative stress at concentrations that do not affect the phosphorylation efficiency.
abstract: Endoxifen (EDX) is a key active metabolite of tamoxifen (TAM) with higher affinity and specificity to estrogen receptors that also inhibits aromatase activity. It is safe and well tolerated by healthy humans, but its use requires toxicological characterization. In this study, the effects of EDX on mitochondria, the primary targets for xenobiotic-induced toxicity, were monitored to clarify its potential side effects. EDX up to 30 nmol/mg protein did not affect the mitochondrial oxidative phosphorylation. At 50 nmol EDX/mg protein, EDX decreased the ADP phosphorylation rate and a partial collapse of mitochondrial membrane potential (Δψ), that parallels a state 4 stimulation, was observed. As the stimulation of state 4 was not inhibited by oligomycin and 50 nmol EDX/mg protein caused a slight decrease in the light scattering of mitochondria, these data suggest that EDX promotes membrane permeabilization to protons, whereas TAM at the same concentration induced mitochondrial membrane disruption. Moreover, EDX at 10 nmol/mg protein prevented and reversed the Ca(2+)-induced depolarization of ΔΨ and the release of mitochondrial Ca(2+), similarly to cyclosporine A, indicating that EDX did not affect Ca(2+) uptake, but directly interfered with the proteins of the mitochondrial permeability transition (MPT) megacomplex, inhibiting MPT induction. At this concentration, EDX exhibited antioxidant activity that may account for the protective effect against MPT pore opening. In conclusion, EDX within the range of concentrations reached in tissues did not significantly damage the bioenergetic functions of mitochondria, contrarily to the prodrug TAM, and prevented the MPT pore opening and the oxidative stress in mitochondria, supporting that EDX may be a less toxic drug for women with breast carcinoma.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal.
authors.forename: Mariana P C
authors.initials: MP
authors.lastname: Ribeiro
authors.forename: Filomena S G
authors.initials: FS
authors.lastname: Silva
authors.forename: Armanda E
authors.initials: AE
authors.lastname: Santos
authors.forename: Maria S
authors.initials: MS
authors.lastname: Santos
authors.forename: José B A
authors.initials: JB
authors.lastname: Custódio
mesh_terms: D000818:Animals; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D010539:Permeability / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D018272:Porins / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D004965:Estrogen Antagonists; D018272:Porins; D020011:Protective Agents; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen