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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Hydroxytamoxifen protects against oxidative stress in brain mitochondria.

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(2+). 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.[1]

References

  1. Hydroxytamoxifen protects against oxidative stress in brain mitochondria. Moreira, P.I., Custódio, J.B., Oliveira, C.R., Santos, M.S. Biochem. Pharmacol. (2004) [Pubmed]
 
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