TY - JOUR T1 - Involvement of Glutathione in Loss of Technetium-99m-MIBI Accumulation Related to Membrane MDR Protein Expression in Tumor Cells JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1214 LP - 1218 VL - 39 IS - 7 AU - Jean-Luc Moretti AU - Muriel Duran Cordobes AU - Anna Starzec AU - Virginie de Beco AU - Jackie Vergote AU - Fatima Benazzouz AU - Brigitte Boissier AU - Hélène Cohen AU - Nour Safi AU - Sophie Piperno-Neumann AU - Jean-Claude Kouyoumdjian Y1 - 1998/07/01 UR - http://jnm.snmjournals.org/content/39/7/1214.abstract N2 - It was reported recently that 99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) uptake is drastically reduced in cancer cells that express the multidrug resistance (MDR) product, Pgp 170 kDa (Pgp), suggesting that 99mTc-MlBI is a transport substrate for this transmembrane glycoprotein. In our study, we explored if another pump, a multidrug resistance-associated protein (MRP), could affect 99mTc-MIBI uptake. In addition, we studied the involvement of intracellular glutathione (GSH) as a modulator of 99mTc-MIBI uptake by both Pgp and MRP proteins. Methods: MDR1 and MRP gene expression in seven human tumor cell lines was determined on a transcriptional level by reverse transcriptase polymerase chain reaction and on a protein level using immunocytochemistry. Technetium-99m-MlBl uptake was quantified by measuring radioactivity retained in the cells incubated at 37°C in the presence or absence of buthionine sulfoximine (BSO), which depletes cellular GSH. The cellular GSH content was determined with Ellman’s reagent. Results: Cell lines were classified according to their phenotypic characteristics: 1/MRP-/Pgp-: breast cancer cells (MCF7), lung carcinoma cells (H69S) and mouth epidermoid tumor cells (KB 3.1), 2/MRP-/Pgp+: MCF7 mdr+, KBA.1; and 3/MRP+/Pgp-: small-cell lung carcinoma (H69 AR and A 549). Technetium-99m-MIBI uptake was significantly lower in cells expressing MRP as well as Pgp compared to MRP/Pgp cells. Depletion of GSH by BSO resulted in an increase of 99mTc-MIBI uptake in multidrug resistant cells over-expressing MRP but not expressing Pgp. Conclusion: Technetium-99m-MIBI is extruded by both Pgp and MRP efflux pumps. However, MRP action is indirect and involves intracellular GSH for a presumed interaction with the 99mTc-MIBI before its efflux. Technetium-99m-MIBI seems to be a good candidate for a noninvasive marker to diagnose MDR1 related to Pgp and MRP expression in tumors of different origin. ER -