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)

Estradiol-17beta-glucuronide (E217G) is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestasis of pregnancy. In the current study, we examined the mechanism of the biliary excretion of E217G and estradiol metabolites in rats. Biliary excretion of tracer doses of [3H]estradiol-17beta-glucuronide and [14C]estradiol or [3H]taurocholate and ]14C]vinblastine, a P-glycoprotein (P-GP) substrate, intravenously administered as a bolus to bile-drained control rats or EHBR was studied. Biliary excretion of E217G and estradiol metabolites EHBR was markedly delayed. Analyses of biliary metabolites after estradiol injection showed less polar conjugates in EHBR. In contrast, the excretion of taurocholate and vinblastine (VLB) was only slightly delayed in EHBR. Although phenothiazine treatment to induce the expression of P-GP increased biliary vinblastine excretion, it did not affect biliary excretion of a tracer dose of [3H]estradiol-17beta-glucuronide. However, phenothiazine treatment inhibited the cholestasis induced by E217G infused at the rate of 0.075 micromol/min/100g for 20 minutes and increased biliary E217G excretion. Sulfobromophthalein infusion (0.2 micromol/min/100 g body 0 weight) markedly inhibited the biliary excretion of E217G and estradiol metabolites, whereas dibromosulfophthalein (DBSP) at the same infusion rate had no effect. These findings indicate that EG17G is excreted into bile by a canalicular organic anion carrier for sulfobromopthalein (BSP), not for DBSP, under physiological conditions, and that P-GP influences E217G excretion only at a high dose. under physiological conditions, and that P-GP influence s E217G excretion only at a high dose.
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PMID:Biliary excretion of estradiol-17 beta-glucuronide in the rat. 861 43

Paclitaxel-resistant HepG2 (PR-HepG2) cells were established by long-term exposure of HepG2 cells to paclitaxel and expression and function of efflux (P-glycoprotein, MRP2) and influx (OATP1B3) transporters for paclitaxel were examined to understand the mechanisms underlying the resistance. mRNA expression of P-glycoprotein (P-gp) increased in PR-HepG2 more than in HepG2 cells, while that of MRP2 did not change. Interestingly, mRNA expression of OATP1B3 drastically decreased in PR-HepG2 cells. [(3)H]Paclitaxel uptake was less in PR-HepG2 than in HepG2 cells and the uptake in both cells increased by metabolic inhibition. The uptake of [(3)H]paclitaxel and rhodamine 123 increased by verapamil, a P-gp inhibitor. Probenecid, an MRP inhibitor, did not affect [(3)H]paclitaxel uptake in both cells. Sulfobromophthalein, an OATP1B3 inhibitor, inhibited [(3)H]paclitaxel uptake in HepG2 but not in PR-HepG2 cells. Cytotoxicity studies showed that the resistance of PR-HepG2 cells to paclitaxel was reversed by verapamil. PR-HepG2 cells showed cross-resistance to doxorubicin, a P-gp substrate, but not to cisplatin. These results indicate that enhanced expression and function of P-gp may be a predominant mechanism of paclitaxel resistance in PR-HepG2 cells and the reduced influx via OATP1B3 may also serve to lower intracellular paclitaxel concentration in cooperation with P-gp-mediated efflux.
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PMID:Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. 1988 Dec 53