{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nABCC4 (MRP4) is an ATP‐dependent efflux pump with a remarkably broad substrate spectrum that includes cyclic nucleotides (cAMP and cGMP), a variety of prostaglandins, conjugated bile acids (often co‐transported with reduced glutathione), steroid and dehydroepiandrosterone conjugates, and nucleoside analog drugs. These studies demonstrate that ABCC4 actively extrudes signaling molecules such as prostaglandin E1/E2 and cyclic nucleotides from diverse cell types—including kidney proximal tubule cells, hepatocytes and platelets—thereby modulating intracellular second messenger levels and contributing to the clearance of xenobiotics and Phase II detoxification products. This substrate versatility underlies its role in cellular mediator storage and elimination, helping to explain phenomena ranging from non‐passive prostaglandin release to the export of antiviral and anticancer nucleoside analogs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its basal transport functions, ABCC4 expression is subject to multifaceted regulation that influences diverse cellular processes and disease states. Its expression and activity are modulated by endogenous signals and exogenous agents—including androgens, dietary polyphenols and nonsteroidal anti‐inflammatory drugs—and by nuclear receptors or transcription factors such as the aryl hydrocarbon receptor, Nrf2 and FXR. In several models, ABCC4 has been implicated in the regulation of intracellular cyclic nucleotide levels that affect vascular smooth muscle proliferation, leukotriene efflux, and even the function of ion channels through molecular association (for example with CFTR). Moreover, its activity in specialized cells such as dendritic cells and in cancer cells (e.g. neuroblastoma) supports roles in immune cell migration and the aggressive behavior of tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, ABCC4 is emerging as a key mediator of drug disposition, resistance and toxicity. Genetic polymorphisms and altered expression of ABCC4 have been associated with treatment outcomes in conditions as varied as antiretroviral therapy, leukemia (where it influences thiopurine and methotrexate efficacy), pancreatic and ovarian cancers, and esophageal carcinoma. ABCC4 contributes to adverse drug reactions—for instance, in the context of tenofovir‐induced renal proximal tubulopathy, cyclophosphamide-induced toxicity, and impaired intestinal drug absorption (as with adefovir dipivoxil)—and plays a role in disorders of purine metabolism linked to hyperuricemia and gout. Furthermore, its dysregulation in brain vasculature may affect blood–brain barrier function in neurodegenerative diseases, while its role in peripheral neuropathy has also been raised. Together, these findings underscore the importance of ABCC4 in mediating not only xenobiotic efflux and cellular signaling but also in shaping clinical responses to chemotherapy and other drug therapies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rémon A M H van Aubel, Pascal H E Smeets, Janny G P Peters, et al. 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