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The use of tamoxifen (TAM) has been questioned on the chemotherapy and chemoprevention of breast cancer due to several estrogen receptor-independent cytotoxic effects. As an alternative, its more active metabolite 4-hydroxytamoxifen (OHTAM) has been proposed with presumed lower side effects. In this work, the potential OHTAM toxicity on rat liver mitochondrial bioenergetics in relation to the multiple deleterious effects of TAM was evaluated. OHTAM, at concentrations lower than those putatively reached in tissues following the administration of TAM, does not induce significant perturbations on the respiratory control ratio (RCR), ADP/O, transmembrane potential (ΔΨ), phosphorylative capacity and membrane integrity of mitochondria. However, at high concentrations, OHTAM depresses the ΔΨ, RCR and ADP/O, affecting the phosphorylation efficiency, as also inferred from the ΔΨ fluctuations and pH changes associated with ADP phosphorylation. Moreover, OHTAM, at concentrations that stimulate the rate of state 4 respiration in parallel to the decrease in the ΔΨ and phosphorylation rate, causes mitochondrial swelling and stimulates both ATPase and citrate synthase activities. However, the OHTAM-observed effects, at high concentrations, are not significant relatively to the damaging effects promoted by TAM and suggest alterations to mitochondrial functions due to proton leak across the mitochondrial inner membrane. [Copyright &y& Elsevier]

Raloxifene (Ral) has estrogenic activity in bone and cardiovascular tissues, but is antiestrogenic in breast and has limited uterotrophic activity in mice. Here we report that Ral stimulates the growth of human endometrial Ishikawa tumors implanted in the mammary fat pad of nude ovariectomized mice. In cultured Ishikawa cells, Ral has agonist effects on transcription mediated by the progesterone receptor, an endogenous estrogen target gene, and on expression of reporter genes containing estrogen response elements (EREs). Both Ral and tamoxifen (Tam), but not estradiol, stimulated transcription mediated by the activator protein 1 at micromolar concentrations. However, this effect correlated with induction of cellular death at high concentrations of Ral or Tam and was not observed at lower concentrations. Our results suggest that Ral has stimulatory effects in Ishikawa cells on both cellular growth and gene transcription, and that EREs can mediate some of these effects. [Copyright &y& Elsevier]