A novel mutant allele of the CYP2A6 gene (CYP2A6* 11) found in a cancer patient who showed poor metabolic phenotype towards tegafur

Satoshi Daigo, Yoshiki Takahashi, Masaki Fujieda, Noritaka Ariyoshi, Hiroshi Yamazaki, Wasaburo Koizumi, Satoshi Tanabe, Katsunori Saigenji, Sekio Nagayama, Kazumasa Ikeda, Yasuhiko Nishioka, Tetsuya Kamataki

Research output: Contribution to journalArticle

110 Citations (Scopus)

Abstract

In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was four-fold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6* 4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6* 11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The Vmax value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the Km values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6* 4C and the new variant CYP2A6* 11.

Original languageEnglish
Pages (from-to)299-306
Number of pages8
JournalPharmacogenetics
Volume12
Issue number4
DOIs
Publication statusPublished - 2002
Externally publishedYes

Fingerprint

Tegafur
Cytochrome P-450 Enzyme System
Alleles
Phenotype
Genes
Neoplasms
Fluorouracil
Thymine Nucleotides
Dihydrouracil Dehydrogenase (NADP)
Amino Acids
Cytosine
NADP
Proline
Serine
Stomach Neoplasms
Capsules
Oxidoreductases

Keywords

  • 5-fluorouracil
  • Cancer
  • Genetic polymorphism
  • Whole deletion

ASJC Scopus subject areas

  • Genetics
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

A novel mutant allele of the CYP2A6 gene (CYP2A6* 11) found in a cancer patient who showed poor metabolic phenotype towards tegafur. / Daigo, Satoshi; Takahashi, Yoshiki; Fujieda, Masaki; Ariyoshi, Noritaka; Yamazaki, Hiroshi; Koizumi, Wasaburo; Tanabe, Satoshi; Saigenji, Katsunori; Nagayama, Sekio; Ikeda, Kazumasa; Nishioka, Yasuhiko; Kamataki, Tetsuya.

In: Pharmacogenetics, Vol. 12, No. 4, 2002, p. 299-306.

Research output: Contribution to journalArticle

Daigo, S, Takahashi, Y, Fujieda, M, Ariyoshi, N, Yamazaki, H, Koizumi, W, Tanabe, S, Saigenji, K, Nagayama, S, Ikeda, K, Nishioka, Y & Kamataki, T 2002, 'A novel mutant allele of the CYP2A6 gene (CYP2A6* 11) found in a cancer patient who showed poor metabolic phenotype towards tegafur', Pharmacogenetics, vol. 12, no. 4, pp. 299-306. https://doi.org/10.1097/00008571-200206000-00005
Daigo, Satoshi ; Takahashi, Yoshiki ; Fujieda, Masaki ; Ariyoshi, Noritaka ; Yamazaki, Hiroshi ; Koizumi, Wasaburo ; Tanabe, Satoshi ; Saigenji, Katsunori ; Nagayama, Sekio ; Ikeda, Kazumasa ; Nishioka, Yasuhiko ; Kamataki, Tetsuya. / A novel mutant allele of the CYP2A6 gene (CYP2A6* 11) found in a cancer patient who showed poor metabolic phenotype towards tegafur. In: Pharmacogenetics. 2002 ; Vol. 12, No. 4. pp. 299-306.
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AU - Ariyoshi, Noritaka

AU - Yamazaki, Hiroshi

AU - Koizumi, Wasaburo

AU - Tanabe, Satoshi

AU - Saigenji, Katsunori

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AU - Ikeda, Kazumasa

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