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In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase

1
Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
2
Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan
3
Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai 980-8573, Japan
4
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(8), 2342; https://doi.org/10.3390/jcm9082342
Received: 12 June 2020 / Revised: 21 July 2020 / Accepted: 21 July 2020 / Published: 22 July 2020
Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms. View Full-Text
Keywords: fluoropyrimidine; dihydropyrimidine dehydrogenase; dihydropyrimidinase; β-ureidopropionase; genetic polymorphism fluoropyrimidine; dihydropyrimidine dehydrogenase; dihydropyrimidinase; β-ureidopropionase; genetic polymorphism
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Hishinuma, E.; Gutiérrez Rico, E.; Hiratsuka, M. In Vitro Assessment of Fluoropyrimidine-Metabolizing Enzymes: Dihydropyrimidine Dehydrogenase, Dihydropyrimidinase, and β-Ureidopropionase. J. Clin. Med. 2020, 9, 2342.

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