Reaction mechanism of melatonin oxidation by reactive oxygen species
ABSTRACT Melatonin (N-acetyl-5-hydroxytryptamine) is a pineal hormone widely known for its antioxidant properties, both in vivo and by direct capture of free radicals in vitro. Although some metabolites and oxidation products of melatonin have been identified, the molecular mechanism by which melatonin exerts its antioxidant properties has not been totally unravelled. This study investigated the reaction mechanism of oxidation of melatonin by radio-induced reactive oxygen species, generated by gamma radiolysis of water for aqueous solutions of melatonin (from 20 to 200 μm), in the presence or absence of molecular oxygen. The hydroxyl radical was found to be the unique species able to initiate the oxidation process, leading to three main products, e.g. N(1)-acetyl-N(2)-formyl-5-methoxykynurenin (AFMK), N(1)-acetyl-5-methoxykynurenin (AMK) and hydroxymelatonin (HO-MLT). The generation of AFMK and HO-MLT strongly depended on the presence of molecular oxygen in solution: AFMK was the major product in aerated solutions (84%), whereas HO-MLT was favoured in the absence of oxygen (86%). Concentrations of AMK remained quite low, and AMK was proposed to result from a chemical hydrolysis of AFMK in solution. A K-value of 1.1 × 10(-4) was calculated for this equilibrium. Both hydrogen peroxide and superoxide dismutase had no effect on the radio-induced oxidation of melatonin, in good accordance for the second case with the poor reactivity of the superoxide anion towards melatonin. Finally, a reaction mechanism was proposed for the oxidation of melatonin in vitro.
- SourceAvailable from: Eun Jung Sohn
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- "Recent evidence suggests that the carcinogenicity of oxidative stress induced by H 2 O 2 is attributable to the inhibition of GJIC   . Melatonin, an indoleamine (N-acetyl-5 methoxytryptamine ), produced especially at night in the pineal gland  , has antioxidant  , anti-inflammatory  , antidepressant , and antitumor activities against various cancers   . Though melatonin was recently shown to regulate GJIC in chick astrocyte , mouse hepatocytes , and MCF-7 breast cancer cells  , the underlying molecular mechanism by melatonin via GJIC regulation in human keratinocyte HaCaT cells still remains unclear. "
ABSTRACT: Though melatonin was known to regulate gap junctional intercellular communication (GJIC) in chick astrocytes and mouse hepatocytes, the underlying mechanism by melatonin was not elucidated in hydrogen peroxide- (H(2)O(2)-) treated HaCaT keratinocyte cells until now. In the current study, though melatonin at 2 mM and hydrogen peroxide (H(2)O(2)) at 300 μM showed weak cytotoxicity in HaCaT keratinocyte cells, melatonin significantly suppressed the formation of reactive oxygen species (ROS) in H(2)O(2)-treated HaCaT cells compared to untreated controls. Also, the scrape-loading dye-transfer assay revealed that melatonin enhances the intercellular communication by introducing Lucifer Yellow into H(2)O(2)-treated cells. Furthermore, melatonin significantly enhanced the expression of connexin 26 (Cx26) and connexin 43 (Cx43) at mRNA and protein levels, but not that of connexin 30 (Cx30) in H(2)O(2)-treated HaCaT cells. Of note, melatonin attenuated the phosphorylation of extracellular signal-regulated protein kinases (ERKs) more than p38 MAPK or JNK in H(2)O(2)-treated HaCaT cells. Conversely, ERK inhibitor PD98059 promoted the intercellular communication in H(2)O(2)-treated HaCaT cells. Furthermore, combined treatment of melatonin (200 μM) and vitamin C (10 μg/mL) significantly reduced ROS production in H(2)O(2)-treated HaCaT cells. Overall, these findings support the scientific evidences that melatonin facilitates gap junctional intercellular communication in H(2)O(2)-treated HaCaT keratinocyte cells via inhibition of connexin 26/43 and ERK as a potent chemopreventive agent.Evidence-based Complementary and Alternative Medicine 11/2012; 2012(1):589365. DOI:10.1155/2012/589365 · 1.88 Impact Factor
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- "Since oxidative stress is considered a key factor in these pathogenic mechanisms, melatonin should reduce the dysfunctional manifestations of Aβ uptake . Melatonin is a proven antioxidant [26, 27], especially in the brain where it reduces molecular damage as demonstrated in animal models of AD [28, 29], as well as in other experimental models of neurodegeneration [30–33]. There are two important clues regarding the role of melatonin in mitochondria rescue, (1) melatonin penetrates mitochondria where it scavenges free radicals [34, 35], (2) melatonin directly inhibits mitochondrial permeability transition pore (MtPTP) . "
ABSTRACT: Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.Oxidative Medicine and Cellular Longevity 05/2012; 2012(11):843649. DOI:10.1155/2012/843649 · 3.36 Impact Factor
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- "Melatonin (MT) is a secretory product of the pineal gland that participates in many important physiological functions, including seasonal reproduction, immunity, and circadian rhythms (Reiter et al. 2010). Numerous reports have documented protective actions of MT in various models of oxidative stress due to its direct free radical scavenger activity, and its indirect antioxidant properties (Bonnefont-rousselot et al. 2011; Galano et al. 2011; Rodriguez et al. 2004; Tan et al. 1993). This indole stimulates the activity of antioxidant enzymes and has the capacity to detoxify other reactive oxygen and nitrogen species including singlet oxygen ( 1 O 2 ), NO, peroxynitrite anion as well as their metabolites peroxynitrous acid and hydrogen peroxide (Tan et al. 2002). "
ABSTRACT: The present study investigated the protective effects of melatonin (MT) against gentamicin (GM)-induced nephrotoxicity and oxidative stress in rats. We also investigated the effects of MT on induction of apoptotic cell death and its potential mechanisms in renal tissues in response to GM treatment. The following four experimental groups were evaluated: (1) vehicle control, (2) MT (15 mg/kg/day), (3) GM (100 mg/kg/day), and (4) GM&MT. GM caused severe nephrotoxicity as evidenced by increased serum blood urea nitrogen and creatinine levels, increased renal tubular cell apoptosis, and increased Bcl2-associated X protein and cleaved caspase-3 protein expression. Additionally, GM treatment caused an increase in levels of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) protein expression in renal tissues. The significant decreases in glutathione content, catalase, superoxide dismutase, glutathione-S-transferase, glutathione peroxidase, and glutathione reductase activities and the increase in malondialdehyde content indicated that GM-induced tissue injury was mediated through oxidative reactions. In contrast, MT treatment protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by the GM treatment. Histopathological studies confirmed the renoprotective effect of MT. These results indicate that MT prevents nephrotoxicity induced by GM in rats, presumably because it is a potent antioxidant, restores antioxidant enzyme activity, and blocks NF-κB and iNOS activation in rat kidney.Archives of Toxicology 04/2012; 86(10):1527-36. DOI:10.1007/s00204-012-0849-8 · 5.98 Impact Factor