Acitretin affects bioenergetics of liver mitochondria and promotes mitochondrial permeability transition: Potential mechanisms of hepatotoxicity

Acitretin is a synthetic retinoid used for severe extensive psoriasis and it has been shown to be an effective and a safe therapeutic drug for other diseases including cancer when used in combination with other agents. However, cases of acitretin-associated liver injury have been documented, but the possible mechanisms of acitretin-associated hepatotoxicity and apoptosis are not entirely clarified. This study reports that mitochondrial dysfunctions may play an important role in liver injury and apoptosis induced by this retinoid. Acitretin (5-20 μM) impaired mitochondrial phosphorylation efficiency as demonstrated by the decrease in the state 3 respiration and ATP levels, and by the increase in the lag phase of ADP phosphorylation cycle, without affecting the membrane potential. Acitretin induced Ca2+-mediated mitochondrial permeability transition (MPT) and decreased the adenine nucleotide translocase (ANT) content. Acitretin-induced MPT was not prevented by thiol group protecting and antioxidant agents, excluding the involvement of oxidative stress mechanisms. However, MPT was prevented by ANT ligands ATP, ADP, tamoxifen and 4-hydroxytamoxifen, implying that the MPT induction by acitretin is mediated by the ANT. ANT plays a major role in promoting apoptosis and ATP synthesis, and it is still considered as a structural component of the pore with a regulatory role in MPT formation. Therefore, our results, including the decrease in the state 3 respiration and the increase in the lag phase of phosphorylation cycle, the ATP depletion and the induction of Ca2+-mediated MPT, indicate that acitretin-associated liver toxicity and apoptosis is possibly related with mitochondrial dysfunctions due to interactions with the ANT. Additionally, the combination of acitretin with other drugs, such as antiestrogens, which are able to inhibit the MPT, may contribute to decrease the toxicity induced by acitretin.