Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism

Letelier, ME; Jara-Sandoval, J; Molina-Berrios, A; Faundez, M; Aracena-Parks, P; Aguilera F.

Abstract

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 Fe3+/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 Fe3+/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 Fe3+/ascorbate-modified melatonin would be directly protecting the CYP450 system through an additional specific mechanism. Pharmacological relevance of this phenomenon is discussed. © 2010 Elsevier Ireland Ltd.

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Título según WOS: Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism
Título según SCOPUS: Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism
Título de la Revista: CHEMICO-BIOLOGICAL INTERACTIONS
Volumen: 185
Número: 3
Editorial: ELSEVIER IRELAND LTD
Fecha de publicación: 2010
Página de inicio: 208
Página final: 214
Idioma: English
URL: http://linkinghub.elsevier.com/retrieve/pii/S0009279710001833
DOI:

10.1016/j.cbi.2010.03.020

Notas: ISI, SCOPUS