PT  - JOURNAL ARTICLE
AU  - Kee Wee Tan
AU  - Angelina Sampson
AU  - Bremansu Osa-Andrews
AU  - Surtaj Hussain Iram
TI  - Calcitriol and Calcipotriol Modulate Transport Activity of ABC Transporters and Exhibit Selective Cytotoxicity in MRP1-overexpressing Cells
AID  - 10.1124/dmd.118.081612
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.081612
4099  - http://dmd.aspetjournals.org/content/early/2018/09/19/dmd.118.081612.short
4100  - http://dmd.aspetjournals.org/content/early/2018/09/19/dmd.118.081612.full
AB  - Efflux transporters P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) can affect the efficacy and toxicity of a wide variety of drugs and are implicated in multidrug resistance (MDR). Eight test compounds, recently identified from an intramolecular FRET-based high throughput screening, were characterized for their interaction with MRP1. We report that the active metabolite of vitamin D3, calcitriol, and its analog calcipotriol are selectively cytotoxic to MRP1-overexpressing cells, besides inhibiting transport function of P-gp, MRP1, and BCRP. Calcitriol and calcipotriol consistently displayed a potent inhibitory activity on MRP1-mediated doxorubicin and calcein efflux in MRP1-overexpressing H69AR and HEK293/MRP1 cells. Vesicular transport studies confirmed a strong inhibitory effect of calcitriol and calcipotriol on MRP1-mediated uptake of tritium-labeled estradiol glucuronide and leukotriene C4. Calcitriol and calcipotriol at non-cytotoxic concentration do not significantly alter mRNA and protein expression levels of MRP1. In cytotoxicity assays, MRP1-overexpressing cells exhibited hypersensitivity towards calcitriol and calcipotriol. Such collateral sensitivity, however, was not observed in HEK293/P-gp and HEK293/BCRP cells, although the vitamin D3 analogs inhibited calcein efflux in P-gp-overexpressing cells, and mitoxantrone efflux in BCRP-overexpressing cells. Our data indicate a potential role of calcitriol and its analogs in targeting malignancies in which MRP1 expression is prominent and contributes to MDR.