1. Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole
- Author
-
Elena García-Martín, Carmen Martínez, Inmaculada Andreu, Miguel A. Miranda, Gemma Amo, Miguel Blanca, Natalia Blanca-López, Gara Esguevillas, José A. G. Agúndez, and María José Torres
- Subjects
Adult ,Male ,Arylamine N-Acetyltransferase ,Dipyrone ,CYP2C19 ,Pharmacology ,Secondary metabolite ,Biology ,Biochemistry ,Polymorphism, Single Nucleotide ,Young Adult ,QUIMICA ORGANICA ,medicine ,Humans ,Allele ,Adverse effect ,CYP2C9 ,Active metabolite ,Alleles ,Cytochrome P-450 CYP2C9 ,Metamizole ,Polymorphism, Genetic ,Acetylation ,Cytochrome P-450 CYP2C19 ,Metabolism ,Toxicity ,Inactivation, Metabolic ,Female ,Polymorphisms ,Biomarkers ,medicine.drug - 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., 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.
- Published
- 2014