Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism

• Published in: Chemico-biological interactions Vol. 185; no. 3; pp. 208 - 214
• Main Authors: Letelier, María Eugenia, Jara-Sandoval, José, Molina-Berríos, Alfredo, Faúndez, Mario, Aracena-Parks, Paula, Aguilera, Felipe
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 14-05-2010
• Subjects: Animals; Antioxidant; Antioxidants - metabolism; Biotransformation; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Fe 3+/ascorbate; Free Radical Scavengers - metabolism; Male; Melatonin; Melatonin - metabolism; Microsomes, Liver - enzymology; Oxidation-Reduction; Rat liver microsomes; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Fe 3+/ascorbate; Melatonin; Reactive oxygen species; Antioxidant; Cytochrome P450; Rat liver microsomes
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2010.03.020

Melatonin, an endogenous hormone, is used as an antioxidant drug in doses quite higher than the endogenous circulating levels of this hormone. Hepatic endoplasmic reticulum contains the cytochrome P450 (CYP450) system, which catalyzes one biotransformation pathway of melatonin; this organelle is also one of the main sources of reactive oxygen species in cells. Therefore, we proposed that the antioxidant activity of this hormone may have a biological relevance in the organelle where it is biotransformed. To evaluate this postulate, we used Fe
3+/ascorbate, an oxygen free radical generating system that leads to lipid peroxidation, loss of protein-thiol content, and activation of UDP-glucuronyltransferase in rat liver microsomes. We found that mM concentrations of melatonin prevented all these oxidative phenomena. We also found that Fe
3+/ascorbate leads to structural alterations in the CYP450 monooxygenase, the enzyme that binds the substrate in the CYP450 system catalytic cycle, probably through direct oxidation of the protein, and also inhibited
p-nitroanisole
O-demethylation, a reaction catalyzed by the CYP450 system. Notably, melatonin prevented both phenomena at μM concentrations. We provide evidence suggesting that melatonin may be oxidized by oxygen free radicals. Thus, we postulate that melatonin may be acting as an oxygen free radical scavenger, and Fe
3+/ascorbate-modified melatonin would be directly protecting the CYP450 system through an additional specific mechanism. Pharmacological relevance of this phenomenon is discussed.