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


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.


CONCLUSIONS
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.
Kim
Sang-Heon
SH
Hanyang University College of Medicine, Seoul, Korea.
Kim
Sang-Hoon
SH
Bahn
Joon-Woo
JW
Kim
Yoon-Keun
YK
Chang
Yoon-Seok
YS
Shin
Eun-Soon
ES
Kim
Youn-Seup
YS
Park
Jae-Seuk
JS
Kim
Bo-Hyung
BH
Jang
In-Jin
IJ
Song
Junghan
J
Kim
Seung-Hyun
SH
Park
Hae-Sim
HS
Min
Kyung-Up
KU
Jee
Young-Koo
YK
D000107:Acetylation; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007538:Isoniazid / Q000097:blood / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid