Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency

Tomiko Kuhara, Chie Ohdoi, Morimasa Ohse, André B.P. Van Kuilenburg, Albert H. Van Gennip, Satoshi Sumi, Tetsuya Ito, Yoshiro Wada, Isamu Matsumoto

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

A rapid yet reliable chemical diagnosis for dihydropyrimidine dehydrogenase (DHPD) deficiency, and possibly dihydropyrimidinase (DHP) deficiency in cancer patients, prior to therapy with pyrimidine analogues such as 5-fluorouracil, is desired for prevention of severe side-effects by these drugs. We have reported the basic separation and quantitation technology for pyrimidine metabolites using gas chromatography-mass spectrometry. A proposal to use the number (n) of standard deviations (SD) above the normal mean, as the index of the excessive urinary excretion of the metabolites appears not to be commonly used. When used, the values were too small, such as two or three, even in genetic disorders. Here, we applied the method to 11 urine specimens from proven cases including two DHP carriers and proved how specific the method is, because "n"-values were markedly large for thymine (T), uracil (U) and/or dihydrothymine (DHT) and dihydrouracil (DHU). In three cases with DHPD deficiency, two were siblings, one with symptoms and the other without, n was 12 for T and 5.9 for U, and 5-hydroxymethyluracil was distinctly detected. These values indicate that the nature of genetic mutation relates closely to the degree of metabolite accumulation in pyrimidine disorders. In six patients with DHP deficiency, n was 8.4-12 for DHT and 7.2-11 for DHU. Many mutations are known for both genes and the assay of residual enzyme activity may be time-consuming or invasive especially for those with DHP deficiency. Thus, this noninvasive yet comprehensive urinalysis has great value for those without a family history, as the first trial, before DNA or the enzyme assay. Our findings again raise the question whether the metabolic block really causes the symptoms found in pyrimidine disorders.

Original languageEnglish
Pages (from-to)107-115
Number of pages9
JournalJournal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
Volume792
Issue number1
DOIs
Publication statusPublished - 15-07-2003
Externally publishedYes

Fingerprint

dihydropyrimidinase
Dihydropyrimidine Dehydrogenase Deficiency
Dihydrouracil Dehydrogenase (NADP)
Metabolites
Gases
Enzyme Assays
Assays
Mutation
Inborn Genetic Diseases
Urinalysis
Thymine
Uracil
Enzyme activity
Drug-Related Side Effects and Adverse Reactions
Fluorouracil
Gas chromatography
Gas Chromatography-Mass Spectrometry
Mass spectrometry
Siblings
Genes

All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Biochemistry
  • Clinical Biochemistry
  • Cell Biology

Cite this

Kuhara, Tomiko ; Ohdoi, Chie ; Ohse, Morimasa ; Van Kuilenburg, André B.P. ; Van Gennip, Albert H. ; Sumi, Satoshi ; Ito, Tetsuya ; Wada, Yoshiro ; Matsumoto, Isamu. / Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency. In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. 2003 ; Vol. 792, No. 1. pp. 107-115.
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Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency. / Kuhara, Tomiko; Ohdoi, Chie; Ohse, Morimasa; Van Kuilenburg, André B.P.; Van Gennip, Albert H.; Sumi, Satoshi; Ito, Tetsuya; Wada, Yoshiro; Matsumoto, Isamu.

In: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, Vol. 792, No. 1, 15.07.2003, p. 107-115.

Research output: Contribution to journalArticle

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T1 - Rapid gas chromatographic-mass spectrometric diagnosis of dihydropyrimidine dehydrogenase deficiency and dihydropyrimidinase deficiency

AU - Kuhara, Tomiko

AU - Ohdoi, Chie

AU - Ohse, Morimasa

AU - Van Kuilenburg, André B.P.

AU - Van Gennip, Albert H.

AU - Sumi, Satoshi

AU - Ito, Tetsuya

AU - Wada, Yoshiro

AU - Matsumoto, Isamu

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Y1 - 2003/7/15

N2 - A rapid yet reliable chemical diagnosis for dihydropyrimidine dehydrogenase (DHPD) deficiency, and possibly dihydropyrimidinase (DHP) deficiency in cancer patients, prior to therapy with pyrimidine analogues such as 5-fluorouracil, is desired for prevention of severe side-effects by these drugs. We have reported the basic separation and quantitation technology for pyrimidine metabolites using gas chromatography-mass spectrometry. A proposal to use the number (n) of standard deviations (SD) above the normal mean, as the index of the excessive urinary excretion of the metabolites appears not to be commonly used. When used, the values were too small, such as two or three, even in genetic disorders. Here, we applied the method to 11 urine specimens from proven cases including two DHP carriers and proved how specific the method is, because "n"-values were markedly large for thymine (T), uracil (U) and/or dihydrothymine (DHT) and dihydrouracil (DHU). In three cases with DHPD deficiency, two were siblings, one with symptoms and the other without, n was 12 for T and 5.9 for U, and 5-hydroxymethyluracil was distinctly detected. These values indicate that the nature of genetic mutation relates closely to the degree of metabolite accumulation in pyrimidine disorders. In six patients with DHP deficiency, n was 8.4-12 for DHT and 7.2-11 for DHU. Many mutations are known for both genes and the assay of residual enzyme activity may be time-consuming or invasive especially for those with DHP deficiency. Thus, this noninvasive yet comprehensive urinalysis has great value for those without a family history, as the first trial, before DNA or the enzyme assay. Our findings again raise the question whether the metabolic block really causes the symptoms found in pyrimidine disorders.

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