Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhodamine 123 is a fluorescent dye that localizes in mitochondria, is a substrate for the multidrug resistance pump, and is retained for long periods of time by carcinoma cells. 17 beta-Estradiol causes GH4C1 cells (rat pituitary tumor cells) to lose rhodamine 123 fluorescence faster than untreated cells. We found that estradiol induces accumulation of the mRNA for the multidrug resistance pump 3-5-fold, with maximum induction occurring within 1 day at 10(-9) M estradiol. Immunoblot analysis demonstrated that estradiol induces a protein of 150 kDa that reacts with an antibody to P-glycoprotein, the multidrug resistance pump. The reduced retention of rhodamine 123 caused by estradiol is prevented by verapamil and cyclosporin, inhibitors of the pump. A clone resistant to the effects of estradiol on rhodamine 123 has greatly reduced levels of mRNA for the pump. The effect of estradiol is more marked on rhodamine 123 retention than it is on that of rhodamine 110 or tetramethylrhodamine methyl ester. We conclude that estradiol enhances rhodamine 123 efflux by inducing the multidrug resistance gene. The specificity for rhodamine 123, compared with other analogs, may be caused by differences in accessibility to the pump.
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PMID:Estradiol induction of rhodamine 123 efflux and the multidrug resistance pump in rat pituitary tumor cells. 842 69

beta-Estradiol 17beta-D-glucuronide (E(2)17G), an endogenous cholestatic metabolite of estradiol, has been identified as a substrate for both hepatic P-glycoprotein (P-gp) and the multispecific organic anion transporter (MOAT), the liver-specific homologue of the multidrug resistance protein. The aim of the present studies was to determine the role of hepatic P-gp and MOAT in E(2)17G-mediated cholestasis and its biliary excretion using the isolated perfused rat liver. A bolus dose of E(2)17G (2 micromol) alone decreased the bile flow maximally from 1.5 to 0.3 microl/min/g liver. In the presence of an infusion of 1.5 microM daunorubicin or 1.0 microM Taxol, P-gp substrates, E(2)17G cholestasis was blocked such that 2 micromol E(2)17G decreased the bile flow from 1.48 to 1.31 or from 1.70 to 1.31 microl/min/g liver, respectively. In the presence of 1 and 3 microM Taxol, the log dose-response curves for E(2)17G cholestasis were shifted to the right 2-fold and 5-fold, respectively, in a parallel manner. Taxol (10 and 50 microM) inhibited the ATP-dependent transport of 10 microM E(2)17G in canalicular plasma membrane vesicles by 46 and 81%, respectively. Daunorubicin (1.5 microM) also shifted the log dose-response curve for E(2)17G cholestasis to the right about 4-fold. Neither Taxol nor daunorubicin decreased the biliary excretion of E(2)17G. Infusion of cyclosporine (6 microM), an inhibitor of both P-gp and MOAT, significantly blocked both E(2)17G cholestasis and biliary excretion, such that 16 micromol E(2)17G decreased the bile flow only 15-20%. In contrast, bromosulfophthalein, a MOAT substrate, had no effect on either E(2)17G-mediated cholestasis or its biliary excretion. These data indicate that P-gp plays an essential role in E(2)17G-mediated cholestasis and suggest that MOAT functions to deliver high concentrations of E(2)17G to P-gp.
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PMID:MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. 889 55

Overexpression of the human multidrug-resistance protein (MRP) causes a form of multidrug resistance similar to that conferred by P-glycoprotein, although the two proteins are only distantly related. In contrast to P-glycoprotein, human MRP has also been shown to be a primary active transporter of a structurally diverse range of organic anionic conjugates, some of which may be physiological substrates. At present, the mechanism by which MRP transports these compounds and mediates multidrug resistance is not understood. With the objective of developing an animal model for studies on the normal functions of MRP and its ability to confer multidrug resistance in vivo, we recently cloned the murine ortholog of MRP (mrp). To assess the degree of functional conservation between mrp and MRP, we directly compared the drug cross-resistance profiles they confer when transfected into human embryonic kidney cells, as well as their ability to actively transport leukotriene C4, 17beta-Estradiol 17beta-(D-glucuronide), and vincristine; mrp and MRP conferred similar drug resistance profiles, with the exception that only MRP conferred resistance to the anthracyclines tested. Consistent with these findings, accumulation of [3H]vincristine and [3H]VP-16 was decreased, and efflux of [3H]vincristine was increased in both murine and human MRP-transfected cell populations, whereas only human MRP-transfected cells displayed decreased accumulation and increased efflux of [3H]daunorubicin. Membrane vesicles derived from both transfected cell populations transported leukotriene C4 in an ATP-dependent manner with comparable efficiency, although the efficiency of 17beta-estradiol 17beta-(D-glucuronide) transport was somewhat higher with MRP transfectants. ATP-dependent transport of vincristine was also observed with vesicles from mrp and MRP transfectants but only in the presence of glutathione. These studies reveal intrinsic differences between the murine and human MRP orthologs with respect to their ability to confer resistance to a major class of chemotherapeutic drugs.
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PMID:Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. 928 95