title: Association of N-acetyltransferase 2 and cytochrome P450 2E1 gene polymorphisms with antituberculosis drug-induced hepatotoxicity in Western India.
abstract: OBJECTIVE
  Tuberculosis (TB) is a major public health problem in India. Despite the treatment availability and monitoring, drug-induced hepatotoxicity (DIH) is a serious concern and can lead to discontinuation of treatment. Anti-TB DIH is well known and can aggravate because of pharmacokinetic and pharmacodynamic interactions. Genetic polymorphism in the drug-metabolizing enzyme genes is an important factor that predisposes certain fraction of the population to drug-induced toxicity. The purpose of this study was to assess the association of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) gene polymorphism with anti-TB DIH in Western Indian population.
  
  
  METHODS
  A prospective cohort study of 215 patients taking treatment against TB was performed. The NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Logistic regression model was used to calculate odds ratio at 95% confidence interval and their respective P values.
  
  
  RESULTS
  The risk of anti-TB DIH was significantly higher in slow acetylator (SA) than in intermediate and rapid acetylator of NAT2 genotypes (odds ratio: 2.3, P = 0.01). We also observed the homozygous point mutation at position 481, associated with higher risk of hepatotoxicity (P < 0.01). The major haplotype NAT2*4 seems to provide protection in DIH compared with non-DIH TB patients (P = 0.04). However, we did not find a significant association between CYP2E1 genotypes and anti-TB DIH.
  
  
  CONCLUSIONS
  Increased susceptibility to isoniazid (INH)-induced hepatotoxicity due to presence of NAT2 SA polymorphism was demonstrated in Western Indian population. NAT2 genotyping can therefore serve as an important tool for identifying patients predisposed to anti-TB DIH.
authors.affiliation: Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India.
authors.forename: Vinod H
authors.initials: VH
authors.lastname: Gupta
authors.forename: Deepak N
authors.initials: DN
authors.lastname: Amarapurkar
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Singh
authors.forename: Preetha
authors.initials: P
authors.lastname: Sasi
authors.forename: Jyotsna M
authors.initials: JM
authors.lastname: Joshi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Baijal
authors.forename: Praveenkumar H
authors.initials: PH
authors.lastname: Ramegowda
authors.forename: Anjali D
authors.initials: AD
authors.lastname: Amarapurkar
authors.forename: Kalpana
authors.initials: K
authors.lastname: Joshi
authors.forename: Pramod P
authors.initials: PP
authors.lastname: Wangikar
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D015331:Cohort Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology; D007538:Isoniazid / Q000009:adverse effects*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D012306:Risk
chemical_list: D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid
keywords: TB patients; drug-induced hepatotoxicity; genetic polymorphisms; slow acetylator