title: Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole.
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.
authors.affiliation: Department of Pharmacology, University of Extremadura, Cáceres, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez
authors.affiliation: Unidad Mixta de Investigación IIS La Fe - UPV, Hospital La Fe, Valencia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Andreu
authors.affiliation: Department of Pharmacology, University of Extremadura, Cáceres, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Amo
authors.affiliation: Department of Chemistry, UPV-CSIC, Polytechnic University of Valencia, Valencia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Miranda
authors.affiliation: Department of Pharmacology, University of Extremadura, Cáceres, Spain.
authors.forename: Gara
authors.initials: G
authors.lastname: Esguevillas
authors.affiliation: Allergy Service, Carlos Haya Hospital, Málaga, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Torres
authors.affiliation: Allergy Service, Hospital Infanta Leonor, Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Blanca-López
authors.affiliation: Allergy Service, Carlos Haya Hospital, Málaga, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanca
authors.affiliation: Department of Biochemistry and Molecular Biology and Genetics, University of Extremadura, Cáceres, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: García-Martín
authors.affiliation: Department of Pharmacology, University of Extremadura, Cáceres, Spain. Electronic address: jagundez@unex.es.
authors.forename: José A G
authors.initials: JA
authors.lastname: Agúndez
mesh_terms: D000107:Acetylation; D000328:Adult; D000483:Alleles; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D004177:Dipyrone / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D004177:Dipyrone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
keywords: Biomarkers; Metabolism; Metamizole; Polymorphisms