Last update 01 Nov 2024

ABCC4

Last update 01 Nov 2024

Basic Info

Synonyms

ABCC4, ATP binding cassette subfamily C member 4, ATP-binding cassette sub-family C member 4

+ [11]

Introduction

ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins (PubMed:11856762, PubMed:12883481, PubMed:12523936, PubMed:12835412, PubMed:15364914, PubMed:15454390, PubMed:16282361, PubMed:17959747, PubMed:18300232, PubMed:26721430). Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4 (PubMed:17959747). Mediates the cotransport of bile acids with reduced glutathione (GSH) (PubMed:12883481, PubMed:12523936, PubMed:16282361). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules (PubMed:11856762, PubMed:12105214, PubMed:15454390, PubMed:18300232, PubMed:17344354). Confers resistance to anticancer agents such as methotrexate (PubMed:11106685).

Drugs associated with ABCC4

ABCC4(Kenjockety)

Target

ABCC4

Mechanism

ABCC4 inhibitors

Active Org.

Kenjockety Biotechnology LLCStartup

Originator Org.

Kenjockety Biotechnology LLCStartup

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ABCC4

100 Translational Medicine associated with ABCC4

0 Patents (Medical) associated with ABCC4

1,348

Literatures (Medical) associated with ABCC4

01 Nov 2024·Arthritis & Rheumatology

Caffeine Inhibits Both Basal and Insulin‐Activated Urate Transport

Article

Author: Mount, David B ; Merriman, Tony R ; Mandal, Asim K ; Merriman, Tony R. ; Choi, Hyon K ; Mandal, Asim K. ; Mount, David B. ; Choi, Hyon K.

ObjectiveCaffeine, an adenosine receptor antagonist, is a potent central nervous system stimulant that also impairs insulin signaling. Recent studies have suggested that coffee consumption lowers serum urate (SU) and protects against gout by unknown mechanisms. We hypothesized that caffeine lowers SU by affecting activity of urate transporters.MethodsWe examined the effect of caffeine and adenosine on basal and insulin stimulation of net 14C‐urate uptake in the human renal proximal tubule cell line PTC‐05 and on individual urate transporters expressed in Xenopus laevis oocytes.ResultsWe found that caffeine and adenosine efficiently inhibited both basal and insulin stimulation of net 14C‐urate uptake mediated by endogenous urate transporters in PTC‐05 cells. In oocytes expressing individual urate transporters, caffeine (>0.2 mM) more efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2, and ABCC4 than did adenosine without significantly affecting URAT1 and OAT10. However, unlike adenosine, caffeine at lower concentrations (<0.2 mM) very effectively inhibited insulin activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2, and ABCC4 by blocking activation of Akt and extracellular signal–regulated kinase.ConclusionWe postulate that inhibition of urate transport activity of the re‐absorptive transporters GLUT9, OAT10, and OAT4 by caffeine is a key mechanism in its urate‐lowering effects. Additionally, the ability of caffeine to block insulin‐activated urate transport by GLUT9a and OAT10 suggests greater relative inhibition of these transporters in hyperinsulinemia.

01 Nov 2024·Pharmacology & Therapeutics

Organic anion transporters in remote sensing and organ crosstalk

Review

Author: Nigam, Sanjay K. ; Nigam, Sanjay K ; Granados, Jeffry C ; Granados, Jeffry C.

The organic anion transporters, OAT1 and OAT3, regulate the movement of drugs, toxins, and endogenous metabolites. In 2007, we proposed that OATs and other SLC22 transporters are involved in "remote sensing" and organ crosstalk. This is now known as the Remote Sensing and Signaling Theory (RSST). In the proximal tubule of the kidney, OATs regulate signaling molecules such as fatty acids, bile acids, indoxyl sulfate, kynurenine, alpha-ketoglutarate, urate, flavonoids, and antioxidants. OAT1 and OAT3 function as key hubs in a large homeostatic network involving multi-, oligo- and monospecific transporters, enzymes, and nuclear receptors. The Remote Sensing and Signaling Theory emphasizes the functioning of OATs and other "drug" transporters in the network at multiple biological scales (inter-organismal, organism, organ, cell, organelle). This network plays an essential role in the homeostasis of urate, bile acids, prostaglandins, sex steroids, odorants, thyroxine, gut microbiome metabolites, and uremic toxins. The transported metabolites have targets in the kidney and other organs, including nuclear receptors (e.g., HNF4a, AHR), G protein-coupled receptors (GPCRs), and protein kinases. Feed-forward and feedback loops allow OAT1 and OAT3 to mediate organ crosstalk as well as modulate energy metabolism, redox state, and remote sensing. Furthermore, there is intimate inter-organismal communication between renal OATs and the gut microbiome. Extracellular vesicles containing microRNAs and proteins (exosomes) play a key role in the Remote Sensing and Signaling System as does the interplay with the neuroendocrine, hormonal, and immune systems. Perturbation of function with OAT-interacting drugs (e.g., probenecid, diuretics, antivirals, antibiotics, NSAIDs) can lead to drug-metabolite interactions. The RSST has general applicability to other multi-specific SLC and ABC "drug" transporters (e.g., OCT1, OCT2, SLCO1B1, SLCO1B3, ABCG2, P-gp, ABCC2, ABCC3, ABCC4). Recent high-resolution structures of SLC22 and other transporters, together with chemoinformatic and artificial intelligence methods, will aid drug development and also lead to a deeper mechanistic understanding of polymorphisms.

01 Nov 2024·International Journal of Biological Macromolecules

Flurbiprofen inhibits cAMP transport by MRP4/ABCC4 increasing the potency of gemcitabine treatment in PDAC cell models

Article

Author: Betina, González ; Carina, Shayo ; Agustín, Gouts ; Héctor, Cerviño Ramiro ; Ana, Sahores ; Natalia, Gómez ; Agustín, Yaneff ; Carlos, Davio

Pancreatic ductal adenocarcinoma (PDAC) remains a highly malignant cancer with a grim prognosis due to its early metastasis and resistance to current chemotherapies, such as Gemcitabine (GEM). We have previously demonstrated that cAMP exclusion by MRP4 is critical for PDAC cell proliferation, establishing this transporter as a promising prognostic marker and therapeutic target. In search for novel therapeutic options to improve GEM efficacy, we conducted a drug repositioning screening to identify potential inhibitors of cAMP transport by MRP4. Several non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the transport of certain MRP4 substrates. In this study, we assessed the efficacy of sixteen NSAIDs in inhibiting cAMP transport mediated by MRP4, identifying seven potent inhibitors based on their IC₅₀ values. The most potent inhibitors were further tested for their effect on cell proliferation and migration. Flurbiprofen emerged as the most potent inhibitor of both MRP4-mediated cAMP transport and cell proliferation. Overexpression of MRP4 in BxPC-3 cells significantly increased GEM resistance, and co-administration of flurbiprofen with GEM markedly enhanced the latter's potency inhibiting PDAC cells proliferation. These findings position flurbiprofen as a potent inhibitor of cAMP transport by MRP4 and a promising adjunctive therapy to enhance GEM effectiveness in PDAC treatment.

News (Medical) associated with ABCC4

15 Dec 2023

·www.prnewswire.com

Three Articles in the Journal of Pharmaceutical Analysis Uncover Previously Unknown Drug and Disease Mechanisms

Researchers identify promising treatment candidates for morphine tolerance and cancer, as well as a biomarker for kidney injury. XI'AN, China, Dec. 15, 2023 /PRNewswire/ -- Long-term use of analgesics such as morphine leads to "tolerance" that reduces drug efficacy. In such cases, dose escalation may be required to achieve the same analgesic effects. The key molecular mechanism of morphine tolerance is its inefficiency in inducing mu-opioid receptor (MOR) endocytosis. None of the currently available strategies to counter morphine tolerance address this underlying molecular mechanism. Moreover, understanding how drugs work is crucial to determine their efficacy. There is also an unmet need for new diagnostic biomarkers that can help identify diseases at an early stage. The October issue of JPA features three articles that address these issues and systematically lay a foundation for future studies and treatment strategies. Continue Reading Opioids, including morphine, are frequently used for managing chronic pain. However, long-term use of morphine leads to tolerance, resulting in reduced analgesic efficacy. The first study aimed to address the issue of morphine tolerance by developing a monoclonal antibody (mAb) named 3A5C7 that precisely targets MOR. The therapeutic efficacy of 3A5C7 and its underlying molecular mechanisms were also evaluated as part of the study. The article was available online in June 2023 and published in Volume 13, Issue 10 in October 2023. The results showed that cell lines HEK293T and SH-SY5Y treated with 3A5C7 exhibited enhanced morphine-induced MOR endocytosis and recycling from cytoplasm to plasma membrane. Further, 3A5C7 diminished hyperactivation of adenylate cyclase, an in vitro biomarker of morphine tolerance. Finally, chronic intrathecal 3A5C7 administration significantly alleviated morphine tolerance in mice, while both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Corresponding author Prof. Zhi-Nan Chen states, "Our newly developed mAb targets MOR with high affinity and specificity, and alleviates morphine tolerance and physical dependence, offering a new therapeutic strategy in the management of chronic pain." In the second study, researchers dug deeper into the anticancer mechanisms of the drug 'pracinostat,' which is a histone deacetylase inhibitor (HDACi). Findings revealed that pracinostat exerts its antitumor effects by inducing excessive asymmetric mitochondrial fission in tumor cells. It switches the scission position from the mitochondrial midzone to the periphery and leads to the selective cell death of tumor cells with high cyclin-dependent kinase 5 (CDK5) levels, representing a promising strategy for anticancer therapy. "Our results revealed the anticancer mechanism of the HDACi pracinostat in colorectal cancer (CRC) via the activation of CDK5-Drp1 signaling to cause selective mitofission-associated cell death (MFAD) of CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment," explains the corresponding author Dr. Yang Wang. In the third study, kynurenic acid was identified as a potential biomarker of renal tubular 'organic anion transporter (OAT)' channels for predicting kidney injury. Serum kynurenic acid concentrations were dramatically increased in rats treated with an OAT1/3 inhibitor and in OAT1/3 double knockout rats. Further, renal kynurenic acid levels were significantly raised in response to a multidrug resistance-associated protein 4 (MRP4), which is key to drug and toxin excretion. Corresponding author Prof. Xinan Wu speculates by saying, "Our findings could aid in adjusting drug dosage or predicting renal injury via OAT channels." Together, these articles offer hope for improved treatment strategies in the future. Reference Title of original paper: Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis Journal: Journal of Pharmaceutical Analysis DOI: Media Contact: Mengjie Wang +86-(0)29-88960092 [email protected] SOURCE Journal of Pharmaceutical Analysis

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ABCC4

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