title: Genetic polymorphisms of drug-metabolizing enzymes and anti-TB drug-induced hepatitis.
abstract: 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.
authors.affiliation: Hanyang University College of Medicine, Seoul, Korea.
authors.forename: Sang-Heon
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Joon-Woo
authors.initials: JW
authors.lastname: Bahn
authors.forename: Yoon-Keun
authors.initials: YK
authors.lastname: Kim
authors.forename: Yoon-Seok
authors.initials: YS
authors.lastname: Chang
authors.forename: Eun-Soon
authors.initials: ES
authors.lastname: Shin
authors.forename: Youn-Seup
authors.initials: YS
authors.lastname: Kim
authors.forename: Jae-Seuk
authors.initials: JS
authors.lastname: Park
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Junghan
authors.initials: J
authors.lastname: Song
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Hae-Sim
authors.initials: HS
authors.lastname: Park
authors.forename: Kyung-Up
authors.initials: KU
authors.lastname: Min
authors.forename: Young-Koo
authors.initials: YK
authors.lastname: Jee
mesh_terms: 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
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid