| Title | Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis. | | Author(s) | Kim SH, Kim SH, Bahn JW, Kim YK, Chang YS, Shin ES, Kim YS, Park JS, Kim BH, Jang IJ, Song J, Kim SH, Park HS, Min KU, Jee YK | | Institution | Hanyang University College of Medicine, Seoul, Korea. | | Source | Pharmacogenomics 2009 Nov; 10(11):1767-79. | | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19891553 |
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