Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis

Abstract

4-Hydroxytamoxifen (OHTAM) is the most active metabolite of the widely prescribed anticancer drug tamoxifen (TAM) used in breast cancer therapy. This work describes the effects of OHTAM on isolated human erythrocytes, using standardized test conditions, to check for a putative contribution to the TAM-induced hemolysis and to study basic mechanisms involved in the interaction of OHTAM with cell membranes. Incubation of isolated human erythrocytes with relatively high concentrations of OHTAM results in a concentration-dependent hemolysis, its hemolytic effect being about one-third of that induced by TAM. OHTAMinduced hemolysis is prevented by either a-tocopherol (a-T) or a-tocopherol acetate (a-TAc) and it occurs in the absence of oxygen consumption and hemoglobin oxidation, ruling out the oxidative damage of erythrocytes. However, OHTAM remarkably increases the osmotic fragility of erythrocytes, increasing the susceptibility of erythrocytes to hypotonic lysis. Additionally, the hemoglobin release induced by OHTAM is preceded by a rapid efflux of intracellular K + . Therefore, our data suggest that OHTAM-induced hemolysis does not contribute to TAM-induced hemolytic anemia and it is a much weaker toxic drug as compared with TAM. Moreover, at variance with the membrane disrupting effects of TAM, OHTAM promotes perturbation of the membrane's backbone region due to its strong binding to proteins with consequent formation of membrane paths of permeability to small solutes and retention of large solutes like hemoglobin, followed by osmotic swelling and cell lysis. The prevention of OHTAM-induced hemolysis by a-T and a-TAc is probably committed to the permeability sealing resulting from structural stabilization of membrane. #

Tamoxifen Suppresses the Immune Response to Plasmodium berghei ANKA and Exacerbates Symptomatology

“…In addition, it is likely that increased parasitaemia also contributed to higher erythrocyte destruction, which decreased haemoglobin concentration. Another possible explanation is that the metabolism of tamoxifen generated 4-OH-tamoxifen, which by binding to erythrocytes, increased its permeability and promoted lysis, as described by Cruz Silva in humans [47]. Our results show tamoxifen aggravates symptomatology in P. berghei ANKA-infected mice.…”

Carboxylic Acids with Certain Molecular Structures Strengthen the Cell Membrane against Osmotic Pressure in Sheep Erythrocytes In Vitro

“…There have been many reports that osmotic fragility (OF) in RBCs is a valuable tool for assessing the actions of various chemicals on the cell membrane in vitro. General [1] and local anesthetics [2], certain kinds of drugs [3] and toxins [4], inorganic [5] and organic compounds [6], as well as substances isolated from plants [7], and crude plant extracts [8], all induce changes in OF in the RBCs of various mammalian species.…”

Monocarboxylic Acids and Dicarboxylic Acids Induce Different Responses in terms of Osmotic Fragility in Rat and Guinea Pig Erythrocytes In vitro

“…Previous reports have shown that osmotic fragility (OF) in erythrocytes is a useful indicator for evaluating the interactions between various substances and the cell membrane in vitro. It was demonstrated that general [1] and local anesthetics [2], some kinds of drugs [3] and toxins [4], as well as inorganic [5] and organic compounds [6] have the potential to change OF in red blood cells (RBCs). The cholesterol content, which is one of major components of the cell membrane, is known to affect membrane fragility in erythrocytes [7,8].…”