Polymorphisms in the CYP1A2 gene and theophylline metabolism in patients with asthma.
BACKGROUND
Cytochrome p450 (CYP) 1A2 gene polymorphisms are thought to be involved in theophylline metabolism.


OBJECTIVE
We analyzed the effect of genetic polymorphisms in the 5'-flanking region to the first intron of the CYP1A2 gene on theophylline metabolism in 75 Japanese patients with asthma and 159 healthy Japanese volunteers.


METHODS
Genetic polymorphisms were detected at 4 sites of the CYP1A2 gene, -2964(G/A) and -1569(T/del) in the 5'-flanking region and 155(T/G) and 731(A/C) in the first intron.


RESULTS
There were no significant differences in the distribution of gene polymorphisms between the asthmatic and control groups. Among asthmatic patients, theophylline clearance was significantly lower in patients with the polymorphism at site -2964(G/A) whose genotype was G/A (0.029 +/- 0.001 L x h(-1) x kg(-1)) or A/A (0.029 +/- 0.002 L x h(-1) x kg(-1)) than in those whose genotype was G/G (0.034 +/- 0.001 L x h(-1) x kg(-1)) (P <.01 and P <.05, respectively). High theophylline clearance levels significantly correlated with age in the G/G subgroup of site -2964(G/A) (P <.05, r = -0.35) but not in the G/A or A/A subgroup.


CONCLUSIONS
Given its potential side effects, theophylline may need to be used with care in patients with the A allele at site -2964(G/A) in the CYP1A2 gene, because theophylline metabolism levels are lower in such patients, particularly in young asthmatic individuals.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. obaseya@yahoo.com
Yasushi
Y
Obase
Terufumi
T
Shimoda
Tetsuya
T
Kawano
Sachiko
S
Saeki
Shin-Ya
SY
Tomari
Kazuko
K
Mitsuta-Izaki
Hiroto
H
Matsuse
Moritoshi
M
Kinoshita
Shigeru
S
Kohno
D024506:5' Flanking Region / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001249:Asthma / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D001499:Bayes Theorem; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D017931:DNA Primers; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013806:Theophylline / Q000493:pharmacokinetics*
D017931:DNA Primers; D004247:DNA; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2