Browsing by Author "Jara Sandoval, Jose"

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    Melatonin protects the cytochrome P450 system through a novel antioxidant mechanism
    (ELSEVIER IRELAND LTD, 2010) Eugenia Letelier, Maria; Jara Sandoval, Jose; Molina Berrios, Alfredo; Faundez, Mario; Aracena Parks, Paula; Aguilera, Felipe
    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 mu M 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. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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    Nitroaryl-1,4-dihydropyridines as antioxidants against rat liver microsomes oxidation induced by iron/ascorbate, Nitrofurantoin and naphthalene
    (PERGAMON-ELSEVIER SCIENCE LTD, 2007) Letelier, Maria Eugenia; Entrala, Paz; Lopez Alarcon, Camilo; Gonzalez Lira, Victor; Molina Berrios, Alfredo; Cortes Troncoso, Juan; Jara Sandoval, Jose; Santander, Paola; Nunez Vergara, Luis
    1,4-Dihydropyridines (DHPs) used in the treatment of cardiovascular diseases, are calcium channel antagonists and also antioxidant agents. These drugs are metabolized through cytochrome P-450 oxidative system, majority localized in the hepatic endoplasmic reticulum. Several lipophilic drugs generate oxidative stress to be metabolized by this cellular system. Thus, DHP antioxidant properties may prevent the oxidative stress associated with hepatic biotransformation of drugs.