title: N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.
abstract: OBJECTIVE
  Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously.
  
  
  METHODS
  Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR.
  
  
  RESULTS
  The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group.
  
  
  CONCLUSIONS
  Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh; Present address: Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605 006, India.
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Adole
authors.affiliation: Department of Neurology, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
authors.forename: Parampreet S
authors.initials: PS
authors.lastname: Kharbanda
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education & Research, Chandigarh, India.
authors.forename: Sadhna
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D014375:Tuberculoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D004338:Drug Combinations; D010672:Phenytoin; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid