title: Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy.
abstract: The relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver biomarkers was investigated in individuals under anti-tuberculosis drug therapy. Tuberculosis outpatients (18-70 y) with (n=59) and without (n=40) mild increase of liver enzymes (MILE) at two-month treatment were selected. Blood samples were obtained for DNA extraction and evaluation of serum markers of liver function. NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms were detected by DNA sequencing, PCR-RFLP, and PCR multiplex. Frequency of NAT2*5/*5 genotype was higher in MILE than in non-MILE group (p=0.04). Patients carrying NAT2*5/*5 genotype had increased susceptibility to MILE (OR: 9.00, 95CI: 1.46-55.48, p=0.018). CYP2E1*5B allele (*1A/*5B plus *5B/*5B genotypes) carriers had a trend for reduced risk for MILE (OR: 0.34, 95CI: 0.11-1.03, p=0.056) that was confirmed by lower levels of liver markers than CYP2E1*1A/*1A carriers after treatment (p<0.05). Moreover, increased post-treatment ALT, AST and total bilirubin were associated with GSTM1*1/GSTT1*1 genotypes (p<0.05). Patients taking CYP2E1 inhibitors had increased susceptibility to MILE (OR: 7.39, 95CI: 1.93-28.29, p=0.003), which was independent of the studied polymorphisms. These results are suggestive that NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms and concomitant use of CYP2E1 inhibitors contribute to the susceptibility to mild alterations in liver enzymes in patients under anti-tuberculosis drug therapy.
authors.affiliation: Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.
authors.forename: Francisco Jose
authors.initials: FJ
authors.lastname: Forestiero
authors.forename: Leticia
authors.initials: L
authors.lastname: Cecon
authors.forename: Mario Hirouki
authors.initials: MH
authors.lastname: Hirata
authors.forename: Fernando Fiuza
authors.initials: FF
authors.lastname: de Melo
authors.forename: Rosilene Fressatti
authors.initials: RF
authors.lastname: Cardoso
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cerda
authors.forename: Rosario Dominguez Crespo
authors.initials: RD
authors.lastname: Hirata
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001938:Brazil; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; D019392:Cytochrome P-450 CYP2E1; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1