Abstract
The multidrug resistance protein 2 (MRP2; ABCC2) is an ATP-binding cassette transporter accepting a diverse range of substrates, including glutathione, glucuronide, and sulfate conjugates of many endo- and xenobiotics. MRP2 generally performs excretory or protective roles, and it is expressed on the apical domain of hepatocytes, enterocytes of the proximal small intestine, and proximal renal tubular cells, as well as in the brain and the placenta. MRP2 is regulated at several levels, including membrane retrieval and reinsertion, translation, and transcription. In addition to transport of conjugates, MRP2 transports cancer chemotherapeutics, uricosurics, antibiotics, leukotrienes, glutathione, toxins, and heavy metals. Several mutagenesis studies have described critical residues for substrate binding and various naturally occurring mutations that eliminate MRP2 expression or function. MRP2 is important clinically as it modulates the pharmacokinetics of many drugs, and its expression and activity are also altered by certain drugs and disease states.
Footnotes
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We gratefully acknowledge Public Health Service Grant GM55343 for support of the work from this laboratory cited here and the Reproductive Sciences Training Program (NIH T32 HD07436) for supporting P.M.G.
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DOI: 10.1124/jpet.102.035014
- Abbreviations:
- MRP
- multidrug resistance-associated protein (lower case refers to nonhuman)
- DNP-SG
- 2,4-dinitrophenyl-S-glutathione
- E217G
- estradiol-17β(β-d-glucuronide)
- GY/TR−
- Groningen yellow/transport deficient Wistar rat
- EHBR
- Eisai hyperbilirubinemic Sprague-Dawley rat
- TM
- transmembrane domain
- MSD
- membrane-spanning domains
- NBD
- nucleotide-binding domain
- DJS
- Dubin-Johnson syndrome
- MDR
- multidrug resistance transporter
- PhIP
- 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
- Bsep
- bile salt export pump
- PCN
- pregnenolone 16α-carbonitrile
- ER-8
- everted repeat with an 8-base pair spacer
- FXR
- farnesoid X receptor
- CAR
- constitutive androstane receptor
- PXR
- pregnane X receptor
- RXR
- retinoid X receptor
- RAR
- retinoic acid receptor
- SN-38
- 7-ethyl-10-hydroxycamptothecin
- BQ-123
- cyclo(l-Leu-d-Trp-d-Asp-l-Pro-d-Val)
- MK571
- 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
- NEM-SG
- N-ethylmaleimide-glutathione
- OATP
- organic anion transporting polypeptide
- Received February 20, 2002.
- Accepted April 24, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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Regulation of Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) and Its Role in Drug Disposition
