Diurnal expression of MRP4 in bone marrow cells underlies the dosing-time dependent changes in the oxaliplatin-induced myelotoxicity
| Autor: | Satoru Koyanagi, Takumi Kanemitsu, Takashi Ogino, Sai Yasukochi, Yuki Kanado, Naoya Matsunaga, Shigehiro Ohdo, Yuya Tsurudome, Mizuki Kato |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Organoplatinum Compounds Science Gene Expression Antineoplastic Agents Bone Marrow Cells ABCC4 Pharmacology Article 03 medical and health sciences Mice 0302 clinical medicine White blood cell Cell Line Tumor medicine Animals Dosing Mice Inbred ICR Multidisciplinary biology Dose-Response Relationship Drug Chemistry Adverse effects Transporter Oxaliplatin Circadian Rhythm Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Toxicity biology.protein Medicine ATP-Binding Cassette Transporters Efflux Bone marrow Drug therapy Multidrug Resistance-Associated Proteins 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-10 (2020) |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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