Multidrug resistance-associated proteins and implications in drug development

Ya He Liu, Yuan Ming Di, Zhi Wei Zhou, Sui Lin Mo, Shu Feng Zhou

Research output: Contribution to journalArticlepeer-review

Abstract

The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood-brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C4. Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug-drug interactions, as well as help overcome drug resistance.

Original languageEnglish (US)
Pages (from-to)115-120
Number of pages6
JournalClinical and Experimental Pharmacology and Physiology
Volume37
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

Keywords

  • Drug development
  • Drug transport
  • Multidrug resistance-associated proteins
  • Pharmacokinetics
  • Toxicity

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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