The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Abstract

Multidrug-resistant protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is distributed in a variety of tissues and a number of cancers. As a drug transporter, MRP4 is responsible for the pharmacokinetics and pharmacodynamics of numerous drugs, especially antiviral drugs, antitumor drugs, and diuretics. In this regard, the functional role of MRP4 is affected by a number of factors, such as genetic mutations; tissue-specific transcriptional regulations; post-transcriptional regulations, including miRNAs and membrane internalization; and substrate competition. Unlike other C family members, MRP4 is in a pivotal position to transport cellular signaling molecules, through which it is tightly connected to the living activity and physiologic processes of cells and bodies. In the context of several cancers in which MRP4 is overexpressed, MRP4 inhibition shows striking effects against cancer progression and drug resistance. In this review, we describe the role of MRP4 more specifically in both healthy conditions and disease states, with an emphasis on its potential as a drug target.

Protein Kinases C-Mediated Regulations of Drug Transporter Activity, Localization and Expression

“…MRP1 exhibits a broad tissue distribution and handles a wide range of xenobiotics, including anionic drugs and drug conjugates [42]. Other members of the MRP/ ABCC family expelling drugs from cells include (1) MRP2 ( ABCC2 ), sharing numerous substrates with MRP1, and expressed in many epithelia and at the canalicular pole of hepatocytes [43]; (2) MRP3 ( ABCC3 ), present at the sinusoidal pole of hepatocytes where it transports xenobiotics from the liver to blood for secondary renal elimination; (3) MRP4 ( ABCC4 ) also expressed at the sinusoidal pole of hepatocytes, but additionally in kidney and at blood–brain barrier, and having a wide substrate specificity, including nucleoside analogues and antiviral drugs [44], and (4) MRP5 ( ABCC5 ), almost ubiquitously expressed in humans and exporting a broad range of natural and xenobiotic compounds such as cyclic guanosine monophosphate, antiviral agents and chemotherapeutic drugs [45]. Like P-gp and MRP1, the ABC transporter breast cancer resistance protein (BCRP/ ABCG2 ) transports both anticancer drugs and non-anticancer drugs and is found at blood–tissue barriers and in the gut and excretory organs like the liver and kidney [46].…”

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…As most of these efflux pumps are up-regulated by Nrf2, using Nrf2 activators may provide an important tool to increase the activity of ABC transporters. MRP4, the multidrug resistance-associated protein 4, encoded by gene ABCC4, is also up-regulated by Nrf2 (Chan et al, 1993;Maher et al, 2007;Yates et al, 2009;Kalra et al, 2011;Kalra et al, 2012) and is able to transport not only drugs, but many different signaling molecules such as cAMP, cGMP, ADP or prostaglandins (PG), playing a very important role in cellular communication and signaling (reviewed in Wen et al, 2015). The clearance of PGs (which are anionic) from the brain to either the blood or the cerebrospinal fluid is mediated by efflux transport processes, with MRP4 playing a central role (Tachikawa et al, 2014).…”

Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport

“…ATP hydrolysis provides the energy for MRP-mediated transmembraneous transport of various substrates (Dallas et al 2006). MRP substrates show high structural diversity, including not only numerous cancer chemotherapeutics (e.g., daunorubicin, methotrexate, cisplatin, or fluoropyrimidines), estradiol derivatives, or glutathione conjugates (Dallas et al 2006), but also antiviral drugs, antibiotics, and various cardiovascular drugs (Wen et al 2015). Among the nine MRP transporters, specifically MRP4 and MRP5 (Dallas et al 2006;Sager 2004) andMRP8 (Guo et al 2003;Sager 2004) accept cyclic nucleotides as substrates.…”