Abstract
Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1- and OATP1B3-mediated transport of the model substrates estradiol-17β-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-trans-p-coumaroyloxy-α-terpineol, which inhibited estradiol-17β-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-α-l-arabinopyranosyl(1→2) α-l-rhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17β-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4- to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased Km), whereas the maximal rate of transport (Vmax) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01GM077336]; and the National Institutes of Health National Center for Research Resources [Grant P20RR021940].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.184564.
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ABBREVIATIONS:
- OATP
- organic anion-transporting polypeptide
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- E3S
- estrone-3-sulfate
- E17β
- estradiol-17β-glucuronide
- compound 4
- 8-trans-p-coumaroyloxy-α-terpineol
- compound 6
- quercetin 3-Ο-α-l-arabinopyranosyl (1→2) α-l-rhamnopyranoside
- MeOH
- methanol
- HEX
- hexane
- BUOH
- butanol
- CC
- column chromatography
- Si-Gel
- silica gel
- EtOAc
- hexanes-ethyl acetate
- Frac
- fraction
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- SN-38
- 7-ethyl-10-hydroxy-camptothecin
- YM758
- (−)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide
- BAPA
- bile acid conjugated N-(3-aminopropyl)-1,3-propanediamine.
- Received May 29, 2011.
- Accepted August 15, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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