title: Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis.
abstract: METHODS
  Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins.
  
  
  OBJECTIVE
  To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients.
  
  
  METHODS
  A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis.
  
  
  RESULTS
  Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01).
  
  
  CONCLUSIONS
  Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.
authors.affiliation: Department of Pharmacology, Faculty of medicine of Sfax, 3029 Sfax, Tunisia. lobna.ben-mahmoud@topnet.tn
authors.forename: L
authors.initials: L
authors.lastname: Ben Mahmoud
authors.forename: H
authors.initials: H
authors.lastname: Ghozzi
authors.forename: A
authors.initials: A
authors.lastname: Kamoun
authors.forename: A
authors.initials: A
authors.lastname: Hakim
authors.forename: H
authors.initials: H
authors.lastname: Hachicha
authors.forename: S
authors.initials: S
authors.lastname: Hammami
authors.forename: Z
authors.initials: Z
authors.lastname: Sahnoun
authors.forename: N
authors.initials: N
authors.lastname: Zalila
authors.forename: H
authors.initials: H
authors.lastname: Makni
authors.forename: K
authors.initials: K
authors.lastname: Zeghal
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 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012307:Risk Factors; D014376:Tuberculosis / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D014416:Tunisia / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid