title: CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis.
abstract: OBJECTIVE
  To determine whether pharmacogenetic tests such as N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genotyping are useful in identifying patients prone to antituberculosis drug-induced hepatotoxicity in a cosmopolite population.
  
  
  METHODS
  In a prospective study we genotyped 89 patients treated with isoniazid (INH) for latent tuberculosis. INH-induced hepatitis (INH-H) or elevated liver enzymes including hepatitis (INH-ELE) was diagnosed based on the clinical diagnostic scale (CDS) designed for routine clinical practice. NAT2 genotypes were assessed by fluorescence resonance energy transfer probe after PCR analysis, and CYP2E1 genotypes were determined by PCR with restriction fragment length polymorphism analysis.
  
  
  RESULTS
  Twenty-six patients (29%) had INH-ELE, while eight (9%) presented with INH-H leading to INH treatment interruption. We report no significant influence of NAT2 polymorphism, but we did find a significant association between the CYP2E1 *1A/*1A genotype and INH-ELE (OR: 3.4; 95% CI:1.1-12; p = 0.02) and a non significant trend for INH-H (OR: 5.9; 95% CI: 0.69-270; p = 0.13) compared with other CYP2E1 genotypes. This test for predicting INH-ELE had a positive predictive value (PPV) of 39% (95% CI: 26-54%) and a negative predictive value (NPV) of 84% (95% CI: 69-94%).
  
  
  CONCLUSIONS
  The genotyping of CYP2E1 polymorphisms may be a useful predictive tool in the common setting of a highly heterogeneous population for predicting isoniazid-induced hepatic toxicity. Larger prospective randomized trials are needed to confirm these results.
authors.affiliation: Central Clinical Chemistry Laboratory, Department of Clinical Pathology, Geneva University Hospital, 24 Micheli-Du-Crest, 1211, Geneva 14, Switzerland. nicolas.vuilleumier@hcuge.ch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vuilleumier
authors.forename: Michel F
authors.initials: MF
authors.lastname: Rossier
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappe
authors.forename: Florence
authors.initials: F
authors.lastname: Degoumois
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Bernadette
authors.initials: B
authors.lastname: Mermillod
authors.forename: Laurent
authors.initials: L
authors.lastname: Nicod
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
authors.forename: Denis
authors.initials: D
authors.lastname: Hochstrasser
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D001483:Base Sequence; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D012150:Polymorphism, Restriction Fragment Length; D011446:Prospective Studies; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D017931:DNA Primers; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid