title: Lower CYP2C9 activity in Turkish patients with Behçet's disease compared to healthy subjects: a down-regulation due to inflammation?
abstract: BACKGROUND
  We previously reported on a Swedish patient with Behçet's disease (BD) who was an ultra-rapid metaboliser of drugs catalysed by CYP2C9. Was this extreme metabolism caused by the disease?
  
  
  OBJECTIVE
  This study aims to compare the genotype/phenotype of CYP2C9 in patients with BD and healthy subjects. As the occurrence of BD is high in Turkey, all subjects were recruited from this country.
  
  
  METHODS
  Genotyping of CYP2C9 was performed using standard PCR-RFLP and allele-specific PCR methods. Phenotyping of CYP2C9 was performed by administration of a 50-mg single oral dose of losartan and by calculating the urinary metabolic ratio (MR) of probe drug to its metabolite E-3174. Quantitation was performed by HPLC.
  
  
  RESULTS
  The frequency of CYP2C9*2 and *3 was not significantly different between the Behçet's disease patients (12.5 and 8.7%) and the healthy subjects (8.9 and 8.2%). The geometric mean losartan MR was higher in the 52 patients (1.75) than in the 96 healthy subjects (1.02) (p = 0.002; t-test). Within the genotypes *1/*1, there was a significant difference of MR between patients and healthy subjects (P = 0.006). All but three of the Behçet's disease patients were treated with colchicine. In nine subsequent patients, we found no significant effect of 2 weeks of treatment with colchicine on the CYP2C9 MR.
  
  
  CONCLUSIONS
  Contrary to expectation, the CYP2C9 activity was lower in Turkish BD patients compared to healthy subjects. As this seems not to be due to colchicine treatment, our hypothesis is that inflammation related to BD might have caused the down-regulation of the CYP2C9 activity due to immune cytokine reactions. The ultra-rapid metabolism of CYP2C9 substrate drugs in the Swedish patient was not due to her BD.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.|Department of Medical Pharmacology, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey.
authors.forename: Mustafa Tugrul
authors.initials: MT
authors.lastname: Goktaş
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Pharmacology at Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186, Stockholm, Sweden. fazleen@puncakalam.uitm.edu.my.|Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia. fazleen@puncakalam.uitm.edu.my.
authors.forename: Fazleen
authors.initials: F
authors.lastname: Hatta
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Karaca
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Said
authors.initials: S
authors.lastname: Kalkisim
authors.affiliation: Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Levent
authors.initials: L
authors.lastname: Kilic
authors.affiliation: Department of Rheumatology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Akdogan
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Melih O
authors.initials: MO
authors.lastname: Babaoglu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Atilla
authors.initials: A
authors.lastname: Bozkurt
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Pharmacology at Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Helldén
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Pharmacology at Karolinska Institutet, Karolinska University Hospital, Huddinge, 14186, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bertilsson
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
authors.forename: Umit
authors.initials: U
authors.lastname: Yasar
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001528:Behcet Syndrome / Q000188:drug therapy / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000652:urine; D007249:Inflammation / Q000378:metabolism; D019808:Losartan / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D013777:Tetrazoles / Q000652:urine; D014421:Turkey
chemical_list: D016207:Cytokines; D007093:Imidazoles; D013777:Tetrazoles; D065729:Cytochrome P-450 CYP2C9; C066026:losartan carboxylic acid; D019808:Losartan; D003078:Colchicine
keywords: Behçet’s disease; CYP2C9; Colchicine; Genotype; Losartan metabolism; Phenotype; Turkish population