title: Association of NAT2, GST and CYP2E1 polymorphisms and anti-tuberculosis drug-induced hepatotoxicity.
abstract: Adherence to the prescribed anti-tuberculosis drug (ATD) treatment is crucial for curing patients with active TB. Anti-tuberculosis drug (ATD) induced hepatotoxicity (ATDH) may contribute to ATD's poor compliance in patients with tuberculosis (TB) as interruption of treatment and the switch to second-line anti-tuberculosis drugs, which is required in patients who do not tolerate standard drugs, may result in a sub-optimal treatment response. Isoniazid (INH) is a part of ATD and involved with ATDH due to toxic metabolites produced on its metabolism in liver, attributed to the variation in enzymes involved in this pathway like N-acetyltransferase 2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferases (GSTs). The present study aimed at analysis of polymorphism at three loci of NAT2, two loci of GST and one locus on CYP2E1 and development of ATDH in patients undergoing ATD therapy. A total of 408 newly diagnosed patients with tuberculosis were enrolled for this study and at the end of sampling, 17 ATDH cases and 391 non-ATDH cases were reported. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by PCR-RFLP and GSTM1 and GSTT1 were evaluated by multiplex PCR. Slow phenotype of NAT2 was found to be a risk factor for developing ATDH when compared to fast acetylators. Slow haplotype C481A590G857 and an intermediate acetylator haplotype T481A590G857 were found to be significantly associated with development of ATDH. GSTM1 and GSTT1 double null genotype was also reported to be associated with ATDH development. The heterozygote genotype 'c1c2' of CYP2E1 was also seen to contribute towards elevated risk of ATDH. 'c2' allele absence in females ATDH group can be considered as a protective factor against development of ATDH. In males, presence of 'c1c2' allele was seen to contribute towards elevated risk of ATDH development.
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India. Electronic address: taurusneha@gmail.com.
authors.forename: Neha
authors.initials: N
authors.lastname: Singla
authors.affiliation: Department of Pulmonary Medicine, PGIMER, Chandigarh 160012, India. Electronic address: dheeraj88@hotmail.com.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Gupta
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India. Electronic address: nitibirbian@yahoo.com.
authors.forename: Niti
authors.initials: N
authors.lastname: Birbian
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India. Electronic address: jagtar@rediffmail.com.
authors.forename: Jagtar
authors.initials: J
authors.lastname: Singh
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics*; D015331:Cohort Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D057915:Drug Substitution; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1
keywords: Anti-tuberculosis drug-induced hepatotoxicity (ATDH); Cytochrome P4502E1 (CYP2E1) and glutathione S-transferases (GSTs); N-acetyltransferase 2 (NAT2); Tuberculosis