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

被引:26
作者
Inarrea, Pedro [1 ]
Casanova, Alvaro [1 ]
Angeles Alava, Maria [1 ]
Iturralde, Maria [1 ]
Cadenas, Enrique [2 ]
机构
[1] Univ Zaragoza, Fac Ciencias, Dept Bioquim & Biol Mol & Celular, E-50009 Zaragoza, Spain
[2] Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90033 USA
关键词
Melatonin; Steroid hormones; Cytochrome P450; Superoxide dismutase; Mitochondria; Intermembrane space; Disulfide bond; Transmembrane potential; Cytochrome c; Apoptosis; Free radicals; CROSS-COMPARTMENT PROTECTION; T-BUTYL HYDROPEROXIDE; SUPEROXIDE-DISMUTASE; REACTIVE OXYGEN; LIVER-MITOCHONDRIA; OXIDATIVE DAMAGE; RAT; MEMBRANE; METABOLISM; TESTOSTERONE;
D O I
10.1016/j.freeradbiomed.2011.03.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 CaCl2-induced loss of transmembrane potential and decreased cytochrome c release. Omeprazole and ketoconazole abrogated both protecting mitochondrial functions promoted by melatonin and steroid hormones. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:1575 / 1581
页数:7
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