Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer.

Autor: Yoshida Y; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Fukuda T; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Tanihara T; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Nishikawa N; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Iwasa S; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Adachi S; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Zaitsu O; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Terada Y; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Tsukamoto R; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Shimoshikiryo H; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Fukuoka K; Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Tsurusaki F; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Hamamura K; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Oyama K; Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Tsuruta A; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Koyanagi S; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan., Matsunaga N; Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address: matunaga@phar.kyushu-u.ac.jp., Ohdo S; Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address: ohdo@phar.kyushu-u.ac.jp.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2024 May 14; Vol. 708, pp. 149813. Date of Electronic Publication: 2024 Mar 20.
DOI: 10.1016/j.bbrc.2024.149813
Abstrakt: The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5, a homolog of human CYP2A6, in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Naoya Matsunaga reports was provided by Kyushu university.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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