Melatonin and steroid hormones activate intermembrane Cu,Zn-superoxide dismutase by means of mitochondrial cytochrome P450

作者：Inarrea Pedro^*; Casanova Alvaro; Angeles Alava Maria; Iturralde Maria; Cadenas Enrique

来源：Free Radical Biology and Medicine, 2011, 50(11): 1575-1581.

DOI：10.1016/j.freeradbiomed.2011.03.003

• Melatonin
• Steroid hormones
• Cytochrome P450
• Superoxide dismutase
• Mitochondria
• Intermembrane space
• Disulfide bond
• Transmembrane potential
• Cytochrome c
• Apoptosis
• Free radicals

Melatonin and steroid hormones are cytochrome P450 (CYP or P450; EC 1.14.14.1) substrates that have antioxidant properties and mitochondria] protective activities. The mitochondrial intermembrane space (IMS) Cu,Zn-superoxide dismutase (SOD1) is activated after oxidative modification of its critical thiol moieties by superoxide anion (O(2)(.-)). This study was aimed at investigating the potential association between the hormonal protective antioxidant actions in mitochondria and the regulation of IMS SOD1 activity. Melatonin, testosterone, dihydrotestosterone, estradiol, and vitamin D induced a sustained activation over time of SOD1 in intact mitochondria, showing a bell-shaped enzyme activation dose response with a threshold at 50 nM and a maximum effect at 1 mu M concentration. Enzyme activation was not affected by furafylline, but it was inhibited by omeprazole, ketoconazole, and tiron, thereby supporting the occurrence of a mitochondrial P450 activity and O(2)(.-) requirements. Mitochondrial P450-dependent activation of IMS SOD1 prevented O(2)(.-)-induced loss of aconitase activity in intact mitochondria respiring in State 3. Optimal protection of aconitase activity was observed at 0.1 mu M P450 substrate concentration, evidencing a likely oxidative effect on the mitochondria] matrix by higher substrate concentrations. Likewise, enzyme activation mediated by mitochondrial P450 activity delayed CaCl(2)-induced loss of transmembrane potential and decreased cytochrome c release. Omeprazole and ketoconazole abrogated both protecting mitochondrial functions promoted by melatonin and steroid hormones.

• 出版日期2011-6-1