P-GLYCOPROTEIN AND ORGANIC CATION SECRETION BY THE MAMMALIAN KIDNEY

On the basis of physiological localization, broad substrate specificit y and energy dependence, the role of the kidney P-glycoprotein was tes ted in the energy-dependent renal secretion of organic cations. P-glyc oprotein-enriched vesicles from CI 1D/VCR [a multidrug-resistant (MDR) cell line] displayed enhanced transport of the MDR drug vinblastine a nd the organic cation cimetidine but not of the organic cation tetraet hylammonium (TEA) over that shown by vesicles prepared from the drug-s ensitive parental line Cl 1D. An outwardly directed proton gradient st imulated TEA and cimetidine uptake by renal brush border membrane vesi cles (BBMV) but this gradient did not enhance the uptake of these orga nic cations into Cl 1D/VCR vesicles. Vinblastine uptake was unaffected by the proton gradient in either vesicle preparation. An outwardly di rected gradient of TEA enhanced the uptake of TEA into renal BBMV but did not do so in the case of Cl 1D/VCR vesicles. These data indicate t hat P-glycoprotein, which is normally energized by ATP hydrolysis, is incapable of catalyzing organic cation/proton exchange or organic cati on/organic cation exchange, properties of the organic cation carrier o f renal proximal tubule BBMV. The MDR substrates and modulators inhibi ted the uptake of vinblastine and cimetidine by Cl 1D/VCR vesicles and the uptake of cimetidine and TEA by renal BBMV. Several organic catio ns studied inhibited TEA and cimetidine uptake by renal BBMV but did n ot inhibit the uptake of vinblastine and cimetidine by Cl 1D/VCR vesic les. Photolabeling of Cl 1D/VCR membranes with [H-3]azidopine could be blocked by MDR drugs and modulators and the organic cations quinine, cyanine 863 and rhodamine 6G but was unaffected by TEA, N-methylnicoti namide and cimetidine. Collectively, these data suggest that, although P-glycoprotein and the renal brush border proton-coupled organic cati on secretory system interact with some of the same compounds, they can be distinguished by their mutually exclusive energy requirements and substrate specificity.