title: Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs.
abstract: OBJECTIVE
  Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH).
  
  
  METHODS
  One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity.
  
  
  RESULTS
  Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH.
  
  
  CONCLUSIONS
  This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.
authors.affiliation: Hemostasis and Thrombosis Laboratory, Hospital of Infectious Diseases Dr. F. J. Muñiz, Buenos Aires, Argentina.
authors.forename: Julián G
authors.initials: JG
authors.lastname: Chamorro
authors.forename: Jorge P
authors.initials: JP
authors.lastname: Castagnino
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Musella
authors.forename: Mabel
authors.initials: M
authors.lastname: Nogueras
authors.forename: Federico M
authors.initials: FM
authors.lastname: Aranda
authors.forename: Ana
authors.initials: A
authors.lastname: Frías
authors.forename: Mabel
authors.initials: M
authors.lastname: Visca
authors.forename: Omar
authors.initials: O
authors.lastname: Aidar
authors.forename: Silvia
authors.initials: S
authors.lastname: Perés
authors.forename: Gabriela F
authors.initials: GF
authors.lastname: de Larrañaga
mesh_terms: D000107:Acetylation; D000328:Adult; D054458:Amplified Fragment Length Polymorphism Analysis; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000378:metabolism; D001118:Argentina / Q000453:epidemiology; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001838:Bolivia / Q000208:ethnology; D056486:Chemical and Drug Induced Liver Injury / Q000208:ethnology / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D016009:Chi-Square Distribution; D003430:Cross-Sectional Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D012307:Risk Factors; D012737:Sex Factors; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human