Multidrug resistance-associated proteins 3, 4, and 5

Area of Science:

• Molecular biology
• Pharmacology
• Biochemistry

Background:

• Multidrug resistance-associated proteins (MRPs) are ATP-binding cassette transporters involved in xenobiotic and endobiotic efflux.
• Recent studies have focused on the functions and substrate specificities of MRP3, MRP4, and MRP5.

Purpose of the Study:

• To summarize recent findings on the transport functions of MRP3, MRP4, and MRP5.
• To clarify the physiological relevance of their substrate transport.

Main Methods:

• Review of recently published experimental results.
• Analysis of data from knockout mouse studies.
• Examination of in vitro transport assays using transfected cells.

Main Results:

• MRP3 transports glutathione, glucuronate, and sulfate conjugates (e.g., estradiol-17beta-glucuronide, bilirubin-glucuronides, etoposide-glucuronide), bile salts, and methotrexate. It mediates efflux of morphine-3-glucuronide and acetaminophen-glucuronide from liver to blood in mice.
• MRP4 and MRP5 transport cyclic nucleotides and nucleotide analogs, but initial high-affinity transport reports were not confirmed. Their affinity for nucleotide analogs is low (K(m) ~1 mM).
• No significant role for MRP3 in bile salt metabolism in mice was found. The in vivo relevance of MRP4/5 transport of analogs and their physiological functions remain undetermined.

Conclusions:

• MRP3 plays a role in eliminating conjugated compounds from the liver, but its function in other tissues like the gut and adrenal cortex needs further study.
• The physiological significance of MRP4 and MRP5 in transporting cyclic nucleotides and nucleotide analogs is currently unclear and requires further research.
• The precise in vivo functions of MRP4 and MRP5, particularly concerning resistance to nucleotide analogs, are yet to be elucidated.