Influence of different chemicals on MDR-1 P-glycoprotein expression and activity in the HK-2 proximal tubular cell line.
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Romiti N, Tramonti G, Chieli E
Influence of different chemicals on MDR-1 P-glycoprotein expression and activity in the HK-2 proximal tubular cell line.
Toxicol Appl Pharmacol. 2002 Sep 1;183(2):83-91.
- PubMed ID
- 12387747 [ View in PubMed]
- Abstract
P-glycoprotein (Pgp), the MDR-encoded membrane transporter, is physiologically expressed in normal tissues with excretory functions, including kidney proximal tubules. In a preliminary report we have shown that HK-2, an immortalized cell line from normal human proximal tubule, expresses a functional Pgp and may be considered a valuable model for in vitro investigations on the Pgp role(s) in human renal pathophysiology. The present investigation was designed to further characterize the properties of HK-2 Pgp by exploring its responsiveness to a variety of exogenous or endogenous modulators. HK-2 cells were cultured in Dulbecco's modified Eagle's medium/Ham's F-12 supplemented with 5% FCS in the absence or in the presence of modulators. Pgp mRNA expression was studied by RT-PCR and the amount of Pgp was determined by Western blotting. Pgp activity was assessed by intracellular rhodamine-123 (R-123) accumulation. RT-PCR showed that HK-2 cells express MDR-1, but not MDR-3. Both MDR-1 Pgp and MDR-1 mRNA were significantly increased in cells cultured in the presence of cyclosporin A (CsA), 1,25(OH)(2)D(3), platelet activating factor, dexamethasone (Dex), or aldosterone. Verapamil (Vp), cimetidine, and trimethoprim did not affect HK-2 Pgp expression. Conversely, 2-acetylaminofluorene strongly downregulated Pgp expression. Vp, CsA, 1,25(OH)(2)D(3) and Dex significantly increased R-123 intracellular retention, indicating the inhibition of Pgp-mediated transport. Drug-pretreated, Pgp-overexpressing cells showed increased Pgp activity and were less susceptible to toxic concentrations of CsA. MDR-1 Pgp in HK-2 appears to be responsive to many compounds, including classical Pgp inhibitors and putative physiological substrates, but some of its pharmacological properties are different from those described in other experimental, in particular nonhuman, cell models.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Aldosterone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Cimetidine P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Dexamethasone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Dexamethasone acetate P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Platelet Activating Factor P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Progesterone P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Aldosterone Experimental Investigational ABCB1 5243 upregulated Aldosterone results in increased expression of ABCB1 mRNA 7q21.12 Cyclosporine Approved Investigational Vet Approved ABCB1 5243 upregulated Cyclosporine results in increased expression of ABCB1 mRNA 7q21.12 Dexamethasone Approved Investigational Vet Approved ABCB1 5243 upregulated Dexamethasone results in increased expression of ABCB1 mRNA 7q21.12 Calcitriol Approved Nutraceutical ABCB1 5243 upregulated Calcitriol results in increased expression of ABCB1 mRNA 7q21.12