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Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

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Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

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dc.contributor.author Martínez, Carmen es_ES
dc.contributor.author Andreu Ros, María Inmaculada es_ES
dc.contributor.author Amo, Gemma es_ES
dc.contributor.author Miranda Alonso, Miguel Ángel es_ES
dc.contributor.author Esguevillas, Gara es_ES
dc.contributor.author Torres, María José es_ES
dc.contributor.author Blanca López, Natalia es_ES
dc.contributor.author Blanca, Miguel es_ES
dc.contributor.author Garcia Martin, Elena es_ES
dc.contributor.author Agúndez, José A.G. es_ES
dc.date.accessioned 2015-06-01T07:12:00Z
dc.date.available 2015-06-01T07:12:00Z
dc.date.issued 2014-12-01
dc.identifier.issn 0006-2952
dc.identifier.uri http://hdl.handle.net/10251/51023
dc.description.abstract Metamizole is a pain-killer drug that has been banned in some countries because of its toxicity, but it is still used in many countries due to its effective analgesic and antispasmodic properties. Although large variability in the biodisposition and adverse effects of metamizole are known, factors underlying this variability are poorly understood. We analyzed the urinary recovery of metabolites, as well as the association of these profiles with genetic and non-genetic factors, in a group of 362 healthy individuals. Gender and functional polymorphisms are strongly related to metabolic profiles. N-demethylation of the active metabolite MAA is diminished in carriers of the CYP2C19*2 allele and in NAT2-slow acetylators. Acetylation of the secondary metabolite AA is decreased in men, in drinkers and in NAT2-slow acetylators with a differential effect of NAT2*5 and NAT2*6 alleles. The formylation of MAA is diminished in older subjects and in carriers of defect CYP2C9 and CYP2C19 alleles. Two novel arachidonoyl metabolites were identified for the first time in humans. Women and NAT2-slow acetylators show higher concentrations, whereas the presence of the rapid CYP2C19*17 allele is associated with lower concentrations of these metabolites. All genetic associations show a gene-dose effect. We identified for the first time genetic and non-genetic factors related to the oxidative metabolism of analgesic drug metamizole, as well as new active metabolites in humans. The phenotypic and genetic factors identified in this study have a potential application as biomarkers of metamizole biotransformation and toxicity. es_ES
dc.description.sponsorship We are grateful to Prof. James McCue for assistance in language editing. Financed by grants PS09/00943, PS09/00469, PI12/00241, PI12/00324 and RETICS RD07/0064/0016 and RD12/0013/0002 and RD12/0013/0009 from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Madrid, Spain; GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. I.A. is supported by a Servet Contract CP11/00154. en_EN
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation Financed by grants PS09/00943, PS09/00469, PI12/00241, PI12/00324 and RETICS RD07/0064/0016 and RD12/0013/0002 and RD12/0013/0009 from Fondo de Investigacio´n Sanitaria, Instituto de Salud Carlos III es_ES
dc.relation GR10068 from Junta de Extremadura, Spain es_ES
dc.relation FEDER funds from the European Union. I.A. is supported by a Servet Contract CP11/00154 es_ES
dc.relation.ispartof Biochemical Pharmacology es_ES
dc.rights Reserva de todos los derechos es_ES
dc.subject Metamizole es_ES
dc.subject Metabolism es_ES
dc.subject Polymorphisms es_ES
dc.subject Biomarkers es_ES
dc.subject.classification QUIMICA ORGANICA es_ES
dc.title Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.bcp.2014.09.005
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Instituto Universitario Mixto de Tecnología Química - Institut Universitari Mixt de Tecnologia Química es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Química - Departament de Química es_ES
dc.description.bibliographicCitation Martínez, C.; Andreu Ros, MI.; Amo, G.; Miranda Alonso, MÁ.; Esguevillas, G.; Torres, MJ.; Blanca López, N.... (2014). Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole. Biochemical Pharmacology. 92(3):457-466. doi:10.1016/j.bcp.2014.09.005 es_ES
dc.description.accrualMethod Senia es_ES
dc.relation.publisherversion http://dx.doi.org/10.1016/j.bcp.2014.09.005 es_ES
dc.description.upvformatpinicio 457 es_ES
dc.description.upvformatpfin 466 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 92 es_ES
dc.description.issue 3 es_ES
dc.relation.senia 288734


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