title: A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur.
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.
authors.affiliation: Laboratory of Drug Metabolism, Division of Pharmacobiodynamics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Daigo
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujieda
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ariyoshi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Wasaburo
authors.initials: W
authors.lastname: Koizumi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanabe
authors.forename: Katsunori
authors.initials: K
authors.lastname: Saigenji
authors.forename: Sekio
authors.initials: S
authors.lastname: Nagayama
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kamataki
mesh_terms: D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000097:blood / Q000378:metabolism; D004338:Drug Combinations; D004926:Escherichia coli; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010094:Oxonic Acid / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics*; D005641:Tegafur / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D014162:Transfection
chemical_list: D000964:Antimetabolites, Antineoplastic; D003374:Coumarins; D017931:DNA Primers; D004273:DNA, Neoplasm; D004338:Drug Combinations; D011725:Pyridines; D011994:Recombinant Proteins; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C104201:gimeracil