title: Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil.
abstract: OBJECTIVE
  To determine the frequency of N-acetyltransferase 2 (NAT2) polymorphisms, the NAT2 acetylation profile and its relation to the incidence of gastrointestinal adverse drug reactions (ADRs), anti-tuberculosis (TB) drug-induced hepatotoxicity, and the clinical risk factors for hepatotoxicity in a population from Brazil.
  
  
  METHODS
  Two hundred and fifty-four Brazilian TB patients using isoniazid (INH), rifampicin (RMP), and pirazinamide (PZA) were tested in a prospective cohort study. NAT2 genotyping was performed by direct PCR sequencing. The association between gastrointestinal ADRs/hepatotoxicity and the NAT2 profile genotype was evaluated by univariate analysis and multiple logistic regression.
  
  
  RESULTS
  Of the 254 patients analyzed, 69 (27.2%) were slow acetylators and 185 (72.8%) were fast acetylators. Sixty-five (25.6%) patients were human immunodeficiency virus (HIV)-positive. Thirty-three (13%) and 14 (5.5%) patients developed gastrointestinal ADR and hepatotoxicity, respectively. Of the 14 hepatotoxicity patients, nine (64.3%) were slow acetylators and five (35.7%) were fast acetylators. Sex, age, presence of hepatitis C virus, alcohol abuse, and baseline aminotransferases were not found to be risk factors for hepatotoxicity. However, logistic regression analysis revealed that slow acetylator status and the presence of HIV (p < 0.05) were independent risk factors for hepatotoxicity.
  
  
  CONCLUSIONS
  Our findings show that HIV-positive patients that have the slow acetylation profile are significantly associated with a higher risk of developing hepatotoxicity due to anti-TB drugs.
authors.affiliation: Centro de Desenvolvimento Científico e Tecnológico da Fundação Estadual de Produção e Pesquisa em Saúde, 5400 Avenida Ipiranga, Porto Alegre, RS 90610-000, Brazil.
authors.forename: L G
authors.initials: LG
authors.lastname: Possuelo
authors.forename: J A
authors.initials: JA
authors.lastname: Castelan
authors.forename: T C
authors.initials: TC
authors.lastname: de Brito
authors.forename: A W
authors.initials: AW
authors.lastname: Ribeiro
authors.forename: P I
authors.initials: PI
authors.lastname: Cafrune
authors.forename: P D
authors.initials: PD
authors.lastname: Picon
authors.forename: A R
authors.initials: AR
authors.lastname: Santos
authors.forename: R L F
authors.initials: RL
authors.lastname: Teixeira
authors.forename: T S
authors.initials: TS
authors.lastname: Gregianini
authors.forename: M H
authors.initials: MH
authors.lastname: Hutz
authors.forename: M L R
authors.initials: ML
authors.lastname: Rossetti
authors.forename: A
authors.initials: A
authors.lastname: Zaha
mesh_terms: D000107:Acetylation; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001938:Brazil; D015331:Cohort Studies; D017931:DNA Primers; D008099:Liver / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D017931:DNA Primers; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human