Genetic polymorphisms of dihydropyrimidinase in a Japanese patient with capecitabine-induced toxicity.
Dihydropyrimidinase (DHP) is the second enzyme in the catabolic pathway of uracil, thymine, and chemotherapeutic fluoropyrimidine agents such as 5-fluorouracil (5-FU). Thus, DHP deficiency might be associated with 5-FU toxicity during fluoropyrimidine chemotherapy. We performed genetic analyses of the family of a patient with advanced colon cancer who underwent radical colectomy followed by treatment with 5-FU prodrug capecitabine and developed severe toxicity attributable to a lack of DHP. We measured urinary uracil and dihydrouracil, and genotyped DPYS in the patient and her family. We also measured the allele frequency of DPYS polymorphisms in 391 unrelated Japanese subjects. The patient had compound heterozygous missense and nonsense polymorphisms comprising c.1001A>G (p.Gln334Arg) in exon 6 and c.1393C>T (p.Arg465Ter) in exon 8, which are known to result in a DHP enzyme with little or no activity. The urinary dihydrouracil/uracil ratio in the patient was 17.08, while the mean ± SD urinary dihydrouracil/uracil ratio in family members who were heterozygous or homozygous for wild-type DPYS was 0.25 ± 0.06. In unrelated subjects, 8 of 391 individuals were heterozygous for the c.1001A>G mutation, while the c.1393C>T mutation was not identified. This is the first report of a DHP-deficient patient with DPYS compound heterozygous polymorphisms who was treated with a fluoropyrimidine, and our findings suggest that polymorphisms in the DPYS gene are pharmacogenomic markers associated with severe 5-FU toxicity in Japanese patients.
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Masahiro
M
Hiratsuka
Department of Surgery, Iwate Prefectural Chubu Hospital, Kitakami, Japan.
Hiroshi
H
Yamashita
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Fumika
F
Akai
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Hiroki
H
Hosono
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Eiji
E
Hishinuma
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Noriyasu
N
Hirasawa
Graduate School of Medicine, Tohoku University, Sendai, Japan.
Takahiro
T
Mori
D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D044466:Asian People / Q000235:genetics*; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects*; D018389:Codon, Nonsense; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery / Q000652:urine; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014498:Uracil / Q000652:urine
D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D014498:Uracil; D000069287:Capecitabine; D000581:Amidohydrolases; C020047:dihydropyrimidinase