Active Efflux of CPT-11 and Its Metabolites in Human KB-Derived Cell Lines
作者： Yuichi Sugiyama , Xiao-Yan Chu , Hiroshi Suzuki , Yukio Kato , Kaoru Ueda
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摘要: To investigate the possible involvement of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and/or other glutathione S-conjugate export pump (GS-X pump) family members on active efflux irinotecan [(7-ethyl-10-[4-(1-piperidino)-1-pipertidino)-1-piperidino]carb onylox y camptothecin (CPT-11)] and its metabolites, as well their contribution to acquisition resistance, we studied uptake CPT-11, metabolite SN-38, glucuronide conjugate (SN38-Glu) using membrane vesicles from human epidermoid KB-3-1-derived cell lines. These lines included KB-C2, C-A500, KCP-4, which overexpress P-gp, MRP, unidentified GS-X pump, respectively. The carboxylate form SN-38 exhibited significant ATP-dependent transport, with a Michaelis constant 17 microM, into C-A500 but not Among these KB-derived cells, CPT-11 was only observed in KB-C2 vesicles. In addition, lactone forms SN38-Glu ATP dependent, although transport activity much higher than that KB-C2. 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed resistance compared KB-3-1, 6.3- 6.8-fold, respectively; corresponding figures for were 12- 27-fold, respectively, whereas those KCP-4 2.3- 20-fold, results suggest MRP P-gp are involved cells. difference substrate specificity among demonstrated.
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