title: Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy.
abstract: OBJECTIVE
  To clarify the association between the cytochrome P450 (CYP) 1A2 genotype with the CYP1A2 phenotype and to search for the CYP1A2*1K haplotype, which has been shown to decrease CYP1A2 inducibility and/or other functional polymorphisms in Japanese.
  
  
  METHODS
  Two polymorphisms, CYP1A2*1C and CYP1A2*1F, were genotyped in 126 patients receiving oral slow-release theophylline (TP) therapy and in 224 healthy volunteers. The CYP1A2 phenotype was assessed by the plasma [1-methyluric acid (1U)+3-methylxanthine (3X)]/TP ratio in the patients. The volunteers were given 150 mg caffeine, and the urine [1X+1U+5-acetylamino-6-amino-3-methyluracil (AAMU)]/17U ratio was used for CYP1A2 phenotyping. CYP1A2 intron 1 and six exons (exon 2-exon 7) were sequenced in the patients whose (1U+3X)/TP ratios were below the mean-2SD of those of all patients, and intron 1 was also sequenced in an additional 20 healthy volunteers exhibiting putative low CYP1A2 activities.
  
  
  RESULTS
  The individual (1U+3X)/TP ratios ranged from 0.007 to 0.21 (a 30-fold difference) in the patients, and the (1X+1U+AAMU)/17U ratios ranged from 1.6 to 112 (a 70-fold difference) in the healthy volunteers. The CYP1A2 activities were not significantly influenced by CYP1A2*1C or CYP1A2*1F. We found no functional polymorphisms by a sequencing analysis.
  
  
  CONCLUSIONS
  These results suggest that the CYP1A2*1C and CYP1A2*1F genotypes are not crucial factors for the variability of CYP1A2 activity and that the CYP1A2*1K haplotype is either nil or only shows a very low frequency in Japanese.
authors.affiliation: Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Kumamoto University, and Department of Medicine, Kumamoto City Hospital, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Takata
authors.forename: Junji
authors.initials: J
authors.lastname: Saruwatari
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nakada
authors.forename: Mizuna
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Fukuda
authors.forename: Fujiho
authors.initials: F
authors.lastname: Tanaka
authors.forename: Shinobu
authors.initials: S
authors.lastname: Takenaka
authors.forename: Shuichi
authors.initials: S
authors.lastname: Mihara
authors.forename: Toru
authors.initials: T
authors.lastname: Marubayashi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002110:Caffeine / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003692:Delayed-Action Preparations; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D012907:Smoking; D013806:Theophylline / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2