Multidrug resistance-associated proteins and implications in drug development

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Multidrug resistance-associated proteins (MRPs) are ATP-binding cassette transporters (ABCC family) with varied tissue expression.
• Nine human MRPs transport diverse endogenous and xenobiotic compounds and their conjugates.

Purpose of the Study:

• To elucidate the distinct functions and substrate specificities of various MRPs.
• To highlight the role of MRPs in drug disposition, toxicity, and drug interactions.
• To emphasize the implication of MRPs in cancer drug resistance.

Main Methods:

• Comparative analysis of MRP substrate specificities (e.g., leukotriene C4, bilirubin glucuronide, cyclic nucleotides, bile acids).
• Review of tissue distribution and physiological functions of different MRP members.
• Examination of MRP involvement in drug efflux from cancer cells.

Main Results:

• MRP1, MRP2, and MRP3 exhibit distinct transport capabilities for organic anions, conjugates, and bile acids.
• MRP4 and MRP5 transport cyclic nucleotides, conferring resistance to nucleotide analogs.
• MRP6 deficiency is linked to pseudoxanthoma elasticum; it transports glutathione conjugates and BQ123.

Conclusions:

• MRPs display significant differences in tissue distribution, substrate specificity, and function.
• MRPs are crucial in drug disposition and excretion, influencing drug toxicity and interactions.
• Understanding MRPs is key to minimizing drug-related adverse effects and overcoming therapeutic resistance in cancer.