title: N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients.
abstract: METHODS
  Isoniazid (INH) is related to the development of hepatotoxicity in some patients.
  
  
  OBJECTIVE
  To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population.
  
  
  METHODS
  Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods.
  
  
  RESULTS
  Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008).
  
  
  CONCLUSIONS
  Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.
authors: Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belem, Para, Brazil.
authors: N P C
authors: NP
authors: Santos
authors: S M
authors: SM
authors: Callegari-Jacques
authors: A K C
authors: AK
authors: Ribeiro Dos Santos
authors: C A
authors: CA
authors: Silva
authors: A C R
authors: AC
authors: Vallinoto
authors: D C R O
authors: DC
authors: Fernandes
authors: D C
authors: DC
authors: de Carvalho
authors: S E B
authors: SE
authors: Santos
authors: M H
authors: MH
authors: Hutz
mesh_terms: D000107:Acetylation; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001938:Brazil / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D016009:Chi-Square Distribution; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D000410:Alanine Transaminase; D007538:Isoniazid