@article {Moretti1214, author = {Jean-Luc Moretti and Muriel Duran Cordobes and Anna Starzec and Virginie de Beco and Jackie Vergote and Fatima Benazzouz and Brigitte Boissier and H{\'e}l{\`e}ne Cohen and Nour Safi and Sophie Piperno-Neumann and Jean-Claude Kouyoumdjian}, title = {Involvement of Glutathione in Loss of Technetium-99m-MIBI Accumulation Related to Membrane MDR Protein Expression in Tumor Cells}, volume = {39}, number = {7}, pages = {1214--1218}, year = {1998}, publisher = {Society of Nuclear Medicine}, abstract = {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{\textdegree}C in the presence or absence of buthionine sulfoximine (BSO), which depletes cellular GSH. The cellular GSH content was determined with Ellman{\textquoteright}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.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/39/7/1214}, eprint = {https://jnm.snmjournals.org/content/39/7/1214.full.pdf}, journal = {Journal of Nuclear Medicine} }