139 480

Cited 49 times in

Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis.

Authors
Kim, SH; Bahn, JW; Kim, YK; Chang, YS; Shin, ES; Kim, YS; Park, JS; Kim, BH; Jang, IJ; Song, J; Park, HS; Min, KU; Jee, YK
Citation
Pharmacogenomics, 10(11):1767-1779, 2009
Journal Title
Pharmacogenomics
ISSN
1462-24161744-8042
Abstract
AIMS: Although some genetic risk factors have been reported for the development of hepatitis due to anti-TB drugs, an extensive candidate gene approach evaluating drug-metabolizing enzymes has not been attempted. This study aimed to investigate the association of genetic polymorphisms in drug-metabolizing enzymes with anti-TB drug-induced hepatitis. MATERIALS & METHODS: We compared genotype distributions of tagging SNPs in promoter, exons and haplotypes in seven drug-metabolizing enzyme genes (CYP2C9, CYP2C19, CYP2D6, CYP2E1, NAT2, UGT1A1 and UGT1A3) between 67 cases and 159 controls. RESULTS: Among four tagging SNPs of N-acetyltransferase 2 (NAT2), -9796T>A in promoter and R197Q were significantly associated (p = 0.0016 and p = 0.0007, respectively). NAT2 haplotype 2 [A-A-A-G] carrying A allele of -9796T>A and A allele of R197Q showed significant association (p = 0.0004). However, there was no significant association between genotypes of other enzyme-metabolizing genes and anti-TB drug-induced hepatitis. The constructs containing -9796A of NAT2 showed significantly lower luciferase activity (p < 0.01), suggesting decreased expression of NAT2. The variant alleles and haplotype 2 showed significantly higher peak serum levels of isoniazid, lower acetyl isoniazid:isoniazid ratio and lower isoniazid clearance compared with wild-types. CONCLUSION: These findings suggest that genetic variants in the promoter and exons of NAT2 increase the risk of anti-TB drug-induced hepatitis by modifying acetylation phenotypes and/or gene expression of NAT2, and there is no essential role for genetic mutation of the other metabolizing enzymes in the development of this adverse reaction.
MeSH terms
AcetylationAntitubercular Agents/adverse effects*Arylamine N-Acetyltransferase/genetics*Drug-Induced Liver Injury/genetics*HaplotypesHumansIsoniazid/bloodIsoniazid/metabolismPolymorphism, Single Nucleotide*
DOI
10.2217/pgs.09.100
PMID
19891553
Appears in Collections:
Journal Papers > Research Organization > Regional Clinical Trial Center
Journal Papers > School of Medicine / Graduate School of Medicine > Allergy
AJOU Authors
김승현박해심
Full Text Link
Files in This Item:
Full-Text Not Available.txtDownload
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse