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Resistance to etoposide has been associated with the overexpression of P-glycoproteinand MRP1 in human tumor cells. However, the role of BCRP in resistance to etoposidehas not been clearly established, especially the significance of arginine 482mutations in drug transport (cellular uptake and efflux). Different levels ofresistance to etoposide have been recently observed in cells expressing BCRP interms of cytotoxicity. The aim of this work was to study the effects of thesemutations on the functional involvement of BCRP in etoposide transport. HEK293cells were transfected with an empty vector (HEK/V), the vector bearing the wild-typeBCRP (HEK/R482), the mutant arginine-482-glycine (HEK/R482G) or the mutant arginine-482-threonine(HEK/R482T). MTT assay was used to study the cytotoxic effect of etoposide and[3H]-etoposide was used to determine cellular drug uptake and efflux. Data showthat HEK/R482G cells displayed the highest levels of resistance to etoposide.Cellular [3H]-etoposide uptake was lower in HEK/R482, HEK/R482G and HEK/R482Tcells compared to HEK/V cells. In addition, cellular [3H]-etoposide uptake inHEK/R482G was the lowest. Drug efflux measurements showed that fumitremorgin Cwas able to increase the residual cellular [3H]-etoposide uptake in BCRP-transfectedcells and especially in HEK/R482G ones. Our data show that the R482G mutationin BCRP is able to increase efflux of etoposide and that mutation analysis atcodon 482 may be of clinical importance in cancers treated with etoposide.

Arginine 482 to glycine mutation in ABCG2/BCRP increases etoposide transport and resistance to the drug in HEK-293 cells