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MUCOSAL BIOLOGY

Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells

Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan

Submitted 30 September 2002 ; accepted in final form 20 March 2003

The transport characteristics of fluorescein methotrexate (F-MTX) were studied by using the rat intestinal crypt cell line IEC-6. Enhanced accumulation of F-MTX at 4°C suggests the existence of an active efflux system. MK-571, an inhibitor of the multidrug resistance-associated protein/ATP binding cassette C (MRP/ABCC) family, also enhanced the accumulation of F-MTX. Transcellular transport of F-MTX from the apical to the basolateral compartment was 2.5 times higher than the opposite direction. This vectorial transport was also reduced by MK-571, indicating the presence of Mrp-type transporter(s) on the basolateral membrane. Mrp3 mRNA was readily detectable, and the protein was localized on the basolateral membrane. Uptake of FMTX into membrane vesicles from IEC-6 cells and Spodoptera frugiperda-9 cells expressing rat Mrp3 were both ATP dependent and saturable as a function of the F-MTX concentration. Similar K_m values (11.0 ± 1.8 and 4.5 ± 1.1 µM) and inhibition profiles by MK-571, estradiol-17-D-glucuronide, and taurocholate for the ATP-dependent transport of F-MTX into these vesicles were obtained. These findings suggest that the efflux of F-MTX is mediated by Mrp3 on the basolateral membrane of IEC-6 cells.

MRP3; intestine; crypt

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