Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11).
Article Details
- CitationCopy to clipboard
Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD
Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11).
Mol Pharmacol. 2005 Feb;67(2):545-57. Epub 2004 Nov 10.
- PubMed ID
- 15537867 [ View in PubMed]
- Abstract
We previously determined that expression of human multidrug resistance protein (MRP) 8, a recently described member of the MRP family of ATP-binding cassette transporters, enhances cellular extrusion of cyclic nucleotides and confers resistance to nucleotide analogs (J Biol Chem 278:29509-29514, 2003). However, the in vitro transport characteristics of the pump have not been determined. In this study, the substrate selectivity and biochemical activity of MRP8 is investigated using membrane vesicles prepared from LLC-PK1 cells transfected with MRP8 expression vector. Expression of MRP8 is shown to stimulate the ATP-dependent uptake of a range of physiological and synthetic lipophilic anions, including the glutathione S-conjugates leukotriene C4 and dinitrophenyl S-glutathione, steroid sulfates such as dehydroepiandrosterone 3-sulfate (DHEAS) and estrone 3-sulfate, glucuronides such as estradiol 17-beta-D-glucuronide (E(2)17betaG), the monoanionic bile acids glycocholate and taurocholate, and methotrexate. In addition, MRP8 is competent in the in vitro transport of cAMP and cGMP, in accord with the results of our previously reported cellular studies. DHEAS, E(2)17betaG, and methotrexate were transported with K(m) and V(max) values of 13.0 +/- 0.8 microM and 34.9 +/- 9.5 pmol/mg/min, 62.9 +/- 12 microM and 62.0 +/- 5.2 pmol/mg/min, and 957 +/- 28 microM and 317 +/- 17 pmol/mg/min, respectively. Based upon the stimulatory action of DHEAS on uptake of E(2)17betaG, the attenuation of this effect at high DHEAS concentrations and the lack of reciprocal promotion of DHEAS uptake by E(2)17betaG, a model involving nonreciprocal constructive interactions between some transport substrates is invoked. These results suggest that MRP8 participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides and indicate that the pump has complex interactions with its substrates.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Conjugated estrogens ATP-binding cassette sub-family C member 11 Protein Humans UnknownSubstrateDetails Cyclic adenosine monophosphate ATP-binding cassette sub-family C member 11 Protein Humans UnknownSubstrateInhibitorDetails Folic acid ATP-binding cassette sub-family C member 11 Protein Humans UnknownSubstrateDetails Indomethacin ATP-binding cassette sub-family C member 11 Protein Humans UnknownInhibitorDetails Methotrexate ATP-binding cassette sub-family C member 11 Protein Humans UnknownSubstrateDetails Probenecid ATP-binding cassette sub-family C member 11 Protein Humans UnknownInhibitorDetails Taurocholic acid ATP-binding cassette sub-family C member 11 Protein Humans UnknownInhibitorDetails - Polypeptides
Name UniProt ID ATP-binding cassette sub-family C member 11 Q96J66 Details