A novel single nucleotide polymorphism altering stability and activity of CYP2A6

Noritaka Ariyoshi, Yu ichi Sawamura, Tetsuya Kamataki

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

CYP2A6 is known as a major cytochrome P450 (CYP) responsible for the oxidation of nicotine and coumarin in humans. In this study, we explored genetic polymorphisms, which reduce CYP2A6 activity in Japanese. Two novel mutations in exon 9 of the CYP2A6 gene were found. A single nucleotide polymorphism of T1412C and G1454T resulted in Ile471Thr and Arg485Leu substitution, respectively. The frequency of the former variant allele was considerably high (15.7%), while the latter variant appeared to be a rare polymorphism. Heterologous expression of CYP2A6 using a cDNA possessing C instead of T-base at codon 471 in Escherichia coli caused remarkable reduction of the stability of holoenzyme at 37°C. Furthermore, this variant enzyme almost lacked nicotine C-oxidase activity, although coumarin 7-hydroxylase activity was still observed. These data suggest that individuals homozygous for the T1412C variant allele or heterozygous for this and a defect allele such as the CYP2A6*4 may be poor metabolizer of nicotine, but not coumarin.

Original languageEnglish
Pages (from-to)810-814
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume281
Issue number3
DOIs
Publication statusPublished - Jan 1 2001
Externally publishedYes

Keywords

  • Allele specific PCR
  • Cytochrome P450
  • Genetic linkage
  • Genetic polymorphism
  • Genotyping
  • Nicotine
  • Poor metabolizers

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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