Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

Abstract The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATPbinding cassette (ABC) efflux transporter encoded by the Abcc...

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Autores principales:	Mizuki Kato, Yuya Tsurudome, Takumi Kanemitsu, Sai Yasukochi, Yuki Kanado, Takashi Ogino, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/44bf9c4e2baa4bbdb723542927ad3ac6
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spelling	oai:doaj.org-article:44bf9c4e2baa4bbdb723542927ad3ac62021-12-02T18:50:43ZDiurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity10.1038/s41598-020-70321-62045-2322https://doaj.org/article/44bf9c4e2baa4bbdb723542927ad3ac62020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70321-6https://doaj.org/toc/2045-2322Abstract The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATPbinding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity.Mizuki KatoYuya TsurudomeTakumi KanemitsuSai YasukochiYuki KanadoTakashi OginoNaoya MatsunagaSatoru KoyanagiShigehiro OhdoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mizuki Kato Yuya Tsurudome Takumi Kanemitsu Sai Yasukochi Yuki Kanado Takashi Ogino Naoya Matsunaga Satoru Koyanagi Shigehiro Ohdo Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
description	Abstract The expression and function of some xenobiotic transporters varies according to the time of day, causing the dosing time-dependent changes in drug disposition and toxicity. Multidrug resistance-associated protein-4 (MRP4), an ATPbinding cassette (ABC) efflux transporter encoded by the Abcc4 gene, is highly expressed in bone marrow cells (BMCs) and protects them against xenobiotics, including chemotherapeutic drugs. In this study, we demonstrated that MRP4 was responsible for the extrusion of oxaliplatin (L-OHP), a platinum (Pt)-based chemotherapeutic drug, from BMCs of mice, and that the efflux transporter expression exhibited significant diurnal variation. Therefore, we investigated the relevance of the diurnal expression of MRP4 in BMCs for L-OHP-induced myelotoxicity in mice maintained under standardized light/dark cycle conditions. After intravenous injection of L-OHP, the Pt content in BMCs varied according to the injection time. Lower Pt accumulation in BMCs was detected in mice after injection of L-OHP at the mid-dark phase, during which the expression levels of MRP4 increased. Consistent with these observations, the myelotoxic effects of L-OHP were attenuated when mice were injected with L-OHP during the dark phase. This dosing schedule also alleviated the L-OHP-induced reduction of the peripheral white blood cell count. The present results suggest that the myelotoxicity of L-OHP is attenuated by optimizing the dosing schedule. Diurnal expression of MRP4 in BMCs is associated with the dosing time-dependent changes in L-OHP-induced myelotoxicity.
format	article
author	Mizuki Kato Yuya Tsurudome Takumi Kanemitsu Sai Yasukochi Yuki Kanado Takashi Ogino Naoya Matsunaga Satoru Koyanagi Shigehiro Ohdo
author_facet	Mizuki Kato Yuya Tsurudome Takumi Kanemitsu Sai Yasukochi Yuki Kanado Takashi Ogino Naoya Matsunaga Satoru Koyanagi Shigehiro Ohdo
author_sort	Mizuki Kato
title	Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
title_short	Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
title_full	Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
title_fullStr	Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
title_full_unstemmed	Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
title_sort	diurnal expression of mrp4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/44bf9c4e2baa4bbdb723542927ad3ac6
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Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity

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