Journal article
Mechanisms underlying the inhibition of the cytochrome P450 system by copper ions
Journal of applied toxicology, v 29(8), pp 695-702
01 Nov 2009
PMID: 19629952
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Copper toxicity has been associated to the capacity of free copper ions to catalyze the production of superoxide anion and hydroxyl radical, reactive species that modify the structure and/or function of biomolecules. In addition, nonspecific Cu2+-binding to thiol enzymes, which modifies their catalytic activities, has been reported. Cytochrome P450 (CYP450) monooxygenase is a thiol protein that binds substrates in the first and limiting step of CYP450 system catalytic cycle, necessary for the metabolism of lipophilic xenobiotics. Therefore, copper ions have the potential to oxidize and bind to cysteinyl residues of this monooxygenase, altering the CYP450 system activity. To test this postulate, we studied the effect of Cu2+ alone and Cu2+/ascorbate in rat liver microsomes, to independently evaluate its nonspecific binding and its pro-oxidant effects, respectively. We assessed these effects on the absorbance spectrum of the monooxygenase, as a measure of structural damage, and p-nitroanisole O-demethylating activity of CYP450 system, as a marker of functional impairment. Data obtained indicate that Cu2+ could both oxidize and bind to some amino acid residues of the CYP450 monooxygenase but not to its heme group. The differences observed between the effects of Cu2+ and Cu2+/ascorbate show that both mechanisms are involved in the catalytic activity inhibition of CYP450 system by copper ions. The significance of these findings on the pharmacokinetics and pharmacodynamics of drugs is discussed. Copyright (C) 2009 John Wiley & Sons, Ltd.
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Details
- Title
- Mechanisms underlying the inhibition of the cytochrome P450 system by copper ions
- Creators
- M. E. Letelier - University of ChileM. Faundez - Pontificia Universidad Católica de ChileJ. Jara-Sandoval - University of ChileA. Molina-Berrios - University of ChileJ. Cortes-Troncoso - University of ChileR. Aracena-Parks - University of ChileR. Marin-Catalan - University of Chile
- Publication Details
- Journal of applied toxicology, v 29(8), pp 695-702
- Publisher
- Wiley
- Number of pages
- 8
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Web of Science ID
- WOS:000272314300008
- Scopus ID
- 2-s2.0-74549135194
- Other Identifier
- 991019415774604721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Toxicology