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.
Highlights
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
To investigate the role of these ATPb inding cassette (ABC) transporters in the extrusion of L-OHP from bone marrow cells (BMCs), we prepared BMCs from mouse femora, and cells were treated with 50 μM L-OHP in the presence of selective inhibitors for P-gp, breast cancer-resistant protein (BCRP), multidrug resistance-associated protein 2 (MRP2), or Multidrug resistanceassociated protein-4 (MRP4)
No significant accumulation of Pt was observed when BMCs were treated by L-OHP together with the P-gp inhibitor PSC83331, BCRP inhibitor Ko14332, or MRP2 inhibitor bromosulfalein[33] (Fig. 1b)
Summary
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. The expression and function of some ABC transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2), and breast cancer-resistant protein (BCRP), exhibit diurnal variation, resulting in dosing time-dependent differences in drug d isposition[10,11,12,13].
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