title: The role of cigarette smoking and liver enzymes polymorphisms in anti-tuberculosis drug-induced hepatotoxicity in Brazilian patients.
abstract: Tuberculosis (TB) is still a major health concern and side-effects related to the treatment, especially drug-induced hepatotoxicity (DIH), should be better investigated. In the present study, a possible association between anti-TB DIH and cigarette smoking, N-acetyltransferase 2 (NAT2), Cytochrome P450 2E1 (CYP2E1) and Cytochrome P450 3A4 (CYP3A4) genotypes was studied in 131 TB Brazilian patients. The NAT2 and CYP3A4 genetic polymorphisms were determined using a polymerase chain reaction (PCR) direct sequencing approach and genetic polymorphisms of CYP2E1 gene were determined by restriction fragment length polymorphism (RFLP). The risk of anti-TB DIH was lower in rapid/intermediate acetylators when compared to slow acetylators (OR: 0.34, CI 95: 0.16-0.71; p < 0.01). A decreased risk of developing anti-TB DIH was also observed in active smokers when compared to non-smokers (OR: 0.28, 95 CI: 0.11-0.64; p < 0.01). Significant association between CYP3A4 genotypes and hepatotoxicity was not observed, as well as between CYP2E1 genotype and hepatotoxicity, whose frequency of patients with wild homozygous was more prevalent. The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require to adjust therapeutic regimen dosages or alarm in case of adverse event developments.
authors.affiliation: Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Camila
authors.initials: C
authors.lastname: Zaverucha-do-Valle
authors.affiliation: Human Genetic Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Sérgio P
authors.initials: SP
authors.lastname: Monteiro
authors.affiliation: Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Genetics and Molecular Biology Department of Federal University of Rio de Janeiro State, Brazil.
authors.forename: Kênia B
authors.initials: KB
authors.lastname: El-Jaick
authors.affiliation: Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Rosadas
authors.affiliation: Tuberculosis and Mycobacteria Clinical Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Marli J M
authors.initials: MJ
authors.lastname: Costa
authors.affiliation: Technical Assistance of Clinical Research and Reference Services, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
authors.forename: Marcel S B
authors.initials: MS
authors.lastname: Quintana
authors.affiliation: Pharmacogenetics Research Laboratory, Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Electronic address: liane.castro@ipec.fiocruz.br.
authors.forename: Liane
authors.initials: L
authors.lastname: de Castro
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D012189:Retrospective Studies; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D014376:Tuberculosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human
keywords: Anti-tuberculosis drug; Cigarette smoking; Hepatotoxicity; Liver enzymes