Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis
- Authors
- Kim, Sang-Heon; Kim, Sang-Hoon; Bahn, Joon-Woo; Kim, Yoon-Keun; Chang, Yoon-Seok; Shin, Eun-Soon; Kim, Youn-Seup; Park, Jae-Seuk; Kim, Bo-Hyung; Jang, In-Jin; Song, Junghan; Kim, Seung-Hyun; Park, Hae-Sim; Min, Kyung-Up; Jee, Young-Koo
- Issue Date
- Nov-2009
- Publisher
- FUTURE MEDICINE LTD
- Keywords
- anti-TB drug; drug-metabolizing enzyme; hepatitis; N-acetyltransferase 2; polymorphism
- Citation
- PHARMACOGENOMICS, v.10, no.11, pp.1767 - 1779
- Indexed
- SCIE
SCOPUS
- Journal Title
- PHARMACOGENOMICS
- Volume
- 10
- Number
- 11
- Start Page
- 1767
- End Page
- 1779
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/175915
- DOI
- 10.2217/PGS.09.100
- ISSN
- 1462-2416
- 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.
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