Inhibition Mechanisms of Mitochondrial Permeability Transition by 4-Hydroxytamoxifen: Protection of NAD(P)H and Thiol Group Oxidation

Abstract

The effects of 4-hydroxytamoxifen (OHTAM) on the mitochondrial permeability transition (MPT) induced by Ca2+ plus peroxynitrite (ONOO−) or phenylarsine oxide (PhAsO) were studied to clarify its mechanisms of MPT inhibition. Ca2+ plus ONOO− induced mitochondrial swelling, membrane potential (Δ Ψ) depolarization, and Ca2+ release. OHTAM, when preincubated with mitochondria, prevents those events, and if added after their induction this drug promotes a time-dependent reversal of Δ Ψ depolarization and Ca2+ release associated with MPT induction, because these events are also inhibited by cyclosporine A (CyA). Preincubation with OHTAM also inhibits thiol group oxidation associated with the MPT promoted by ONOO− and allows the NAD(P)+ to recover their reduced state faster and in a higher extension. The mitochondrial swelling and Ca2+ release after MPT induction with Ca2+ plus PhAsO are inhibited by OHTAM; similarly to CyA, the oxidation of NAD(P)H induced by this combination is also inhibited. According to these data, the MPT inhibition by OHTAM may be related to its antioxidant capacity and the binding to target protein components of the MPT, preventing the oxidation of NAD(P)H and thiol groups, an event that increases the sensitivity to MPT induction.