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

Abstract

Melatonin and steroid hormones are cytochrome P450 (CYP or P450; EC 1.14.14.1) substrates that have antioxidant properties and mitochondrial protective activities. IMS (Mitochondrial intermembrane space) SOD1 (Cu,Zn-superoxide dismutase) is activated following oxidative modification of its critical thiol moieties by superoxide anion (O2.− ). This study was aimed at investigating the potential association between the hormonal protective antioxidant actions in mitochondria and 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 μM 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 O2.− requirements. Mitochondrial P450–dependent activation of IMS SOD1 prevented O2.− -induced loss of aconitase activity in intact mitochondria respiring at state 3 respiration. Optimal protection of aconitase activity was observed at 0.1 μM P450 substrate concentration evidencing a likely oxidative effect on the mitochondrial matrix by higher substrate concentrations. Likewise, enzyme activation mediated by mitochondrial P450 activity delayed CaCl2-induced loss of trans-membrane potential, and decreased cytochrome c release. Omeprazole and ketoconazole abrogated both protecting mitochondrial functions promoted by melatonin and steroid hormones.

New Evidence for Cross Talk between Melatonin and Mitochondria Mediated by a Circadian-Compatible Interaction with Nitric Oxide

“…or chronically administered to the animals in drinking water, and their liver or brain mitochondria were isolated and assayed [42–44]. Protocols were compatible with a blood circulating drug concentration, variable [45–47], though somewhat higher, than the ~10 −9 M physiological one [48]. …”

Preventing and Experiencing Ischemic Heart Disease as a Woman: State of the Science

“…156 In addition, estradiol increases NO chronically since it upregulates synthesis of eNOS via estrogen response elements that would promote vasodilation and thus reductions in BP. 157 Estradiol is a modest antioxidant since it upregulates superoxide dismutase, 158 which removes superoxide which reduces oxidative stress. Superoxide binds to NO with high affinity, and thus renders NO unavailable for vasodilation.…”

Hypertension in Postmenopausal Women

“…Both acute and chronic effects of estradiol on NO promote vasodilation and thus reductions in BP [76]. Estradiol is a modest antioxidant, as it upregulates superoxide dismutase [77], which removes superoxide, which reduces oxidative stress. Superoxide binds to NO with high affinity and thus renders NO unavailable for vasodilation [31, 32].…”