Mechanisms underlying the inhibition of the cytochrome P450 system by copper ions

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dc.contributor.authorLetelier, M. E.
dc.contributor.authorFaundez, M.
dc.contributor.authorJara Sandoval, J.
dc.contributor.authorMolina Berrios, A.
dc.contributor.authorCortes Troncoso, J.
dc.contributor.authorAracena Parks, R.
dc.contributor.authorMarin Catalan, R.
dc.date.accessioned2024-01-10T13:14:46Z
dc.date.available2024-01-10T13:14:46Z
dc.date.issued2009
dc.description.abstractCopper 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.
dc.fechaingreso.objetodigital2024-04-27
dc.format.extent8 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1002/jat.1460
dc.identifier.eissn1099-1263
dc.identifier.issn0260-437X
dc.identifier.pubmedidMEDLINE:19629952
dc.identifier.urihttps://doi.org/10.1002/jat.1460
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/78438
dc.identifier.wosidWOS:000272314300008
dc.information.autorucQuímica;Faúndez M;S/I;174901
dc.issue.numero8
dc.language.isoen
dc.nota.accesoContenido parcial
dc.pagina.final702
dc.pagina.inicio695
dc.publisherWILEY
dc.revistaJOURNAL OF APPLIED TOXICOLOGY
dc.rightsacceso restringido
dc.subjectcopper toxicology
dc.subjectcytochrome P450
dc.subjectoxidative stress
dc.subjectrat liver microsomes
dc.subjectdrug metabolism
dc.subjectMICROSOMAL UDP-GLUCURONOSYLTRANSFERASE
dc.subjectMONOXIDE-BINDING PIGMENT
dc.subjectNF-KAPPA-B
dc.subjectCU(I)-GLUTATHIONE COMPLEX
dc.subjectLIVER MICROSOMES
dc.subjectIRON OVERLOAD
dc.subjectRAT-LIVER
dc.subjectGLUTATHIONE
dc.subjectMETABOLISM
dc.subjectTRANSPORT
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleMechanisms underlying the inhibition of the cytochrome P450 system by copper ions
dc.typeartículo
dc.volumen29
sipa.codpersvinculados174901
sipa.indexWOS
sipa.trazabilidadCarga SIPA;09-01-2024
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