title: N-acetyltransferase 2, cytochrome P4502E1 and glutathione S-transferase genotypes in antitubercular treatment-induced hepatotoxicity in North Indians.
abstract: OBJECTIVE
  Tuberculosis (TB) is a major cause of illness and death in developing countries. Hepatotoxicity is a serious side effect of antituberculosis treatment (ATT). NAT2, CYP2E1 and glutathione S-transferase (GST) gene polymorphisms may play an important role in ATT-induced hepatotoxicity. So, elucidating the genetics involved in anti-TB drug-induced hepatotoxicity in patients would be of utmost clinical significance. Therefore, the objective of the study was to elucidate the role of NAT2, CYP2E1 and GST gene polymorphisms in ATT-induced hepatotoxicity in North Indian patients.
  
  
  METHODS
  Three hundred patients with pulmonary and extra-pulmonary TB were enrolled. Total genomic DNA was isolated from each patient's peripheral lymphocytes using phenol-chloroform method, and genetic polymorphic analysis for N-acetyltransferase 2 (NAT2), cytochrome P4502E1 (CYP2E1) and GST was performed by polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP).
  
  
  CONCLUSIONS
  Of the 300 patients, 185 were males and 115 females. Among them, 33 males and 22 females developed ATT-induced hepatotoxicity. There were significant increases in alanine aminotransferase, aspartate aminotransferase and bilirubin levels in patients with ATT-induced hepatotoxicity at 1 month of treatment. NAT2 5/7 and 6/7 were significantly higher in hepatotoxicity patients as compared to the non-hepatotoxicity group. c1/c1 allele of CYP2E1 gene was lower (50·9%) in ATT-induced hepatotoxicity patients as compared to non-hepatotoxicity patients (61·2%), whereas c1/c2 and c2/c2 alleles were higher, but not statistically significant. GSTM1 was significantly higher in hepatotoxicity patients as compared to non-hepatotoxicity patients, whereas GSTT1 and GSTT1/M1 were lower, but not statistically significant.
  
  
  CONCLUSIONS
  This study indicates that patients with slow-acetylator genotypes (NAT2 5/7, 6/7) and GSTM1 allele of GST enzyme were at higher risk of ATT-induced hepatotoxicity.
authors.affiliation: Department of Super Specialty Gastroenterology, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
authors.forename: S V
authors.initials: SV
authors.lastname: Rana
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: R P
authors.initials: RP
authors.lastname: Ola
authors.forename: J K
authors.initials: JK
authors.lastname: Kamboj
authors.forename: A
authors.initials: A
authors.lastname: Malik
authors.forename: R K
authors.initials: RK
authors.lastname: Morya
authors.forename: S K
authors.initials: SK
authors.lastname: Sinha
mesh_terms: D000328:Adult; D000483:Alleles; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007194:India; D008297:Male; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase
keywords: N-acetyltransferase-2; antitubercular treatment; cytochrome P4502E1; glutathione S-transferase; polymorphism