Phenotype-genotype analysis of CYP1A2 in Japanese patients receiving oral theophylline therapy.
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.
Takata
Keiji
K
Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Kumamoto University, and Department of Medicine, Kumamoto City Hospital, Japan.
Saruwatari
Junji
J
Nakada
Naoyuki
N
Nakagawa
Mizuna
M
Fukuda
Koichiro
K
Tanaka
Fujiho
F
Takenaka
Shinobu
S
Mihara
Shuichi
S
Marubayashi
Toru
T
Nakagawa
Kazuko
K
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
D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D002110:Caffeine; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2