Role of MRP transporters in regulating antimicrobial drug inefficacy and oxidative stress-induced pathogenesis during HIV-1 and TB infections

Abstract

Multi-Drug Resistance Proteins (MRPs) are members of the ATP binding cassette (ABC) drug-efflux transporter superfamily. MRPs are known to regulate the efficacy of a broad range of anti-retroviral drugs (ARV) used in highly active antiretroviral therapy (HAART) and antibacterial agents used in Tuberculus Bacilli (TB) therapy. Due to their role in efflux of glutathione (GSH) conjugated drugs, MRPs can also regulate cellular oxidative stress, which may contribute to both HIV and/or TB pathogenesis. This review focuses on the characteristics, functional expression, and modulation of known members of the MRP family in HIV infected cells exposed to ARV drugs and discusses their known role in drug-inefficacy in HIV/TB-induced dysfunctions. Currently, nine members of the MRP family (MRP1-MRP9) have been identified, with MRP1 and MRP2 being the most extensively studied. Details of the other members of this family have not been known until recently, but differential expression has been documented in inflammatory tissues. Researchers have found that the distribution, function, and reactivity of members of MRP family vary in different types of lymphocytes and macrophages, and are differentially expressed at the basal and apical surfaces of both endothelial and epithelial cells. Therefore, the prime objective of this review is to delineate the role of MRP transporters in HAART and TB therapy and their potential in precipitating cellular dysfunctions manifested in these chronic infectious diseases. We also provide an overview of different available options and novel experimental strategies that are being utilized to overcome the drug resistance and disease pathogenesis mediated by these membrane transporters.

Metabolism of 4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone by Retinal Pigmented Epithelial Cells

“…Figure 12 depicts the putative generation HOHA-lactone in a retinal rod cell, and its diffusion into an adjacent RPE cell where it is metabolized and from which the metabolites are secreted into the extracellular matrix. While drug-efflux transporters of GSH conjugated drugs, i.e., multi-drug resistance proteins, are well known 19 and expressed in RPE, 20 the identity of the transporter(s) involved in the metabolism of HOHA-lactone remain(s) unknown. The possibility that HOHA-lactone or its GSH conjugates induce expression of the transporter(s) or, by covalent modification, decrease or abolish the activity of the transporter(s) are also important questions for further investigation.…”

Major obstacles to doxorubicin therapy: Cardiotoxicity and drug resistance

“…95 ABC transporters such as the MRPs and P-gp are responsible for transporting different drugs like nucleoside analogs, natural anticancer agents, tyrosine kinase inhibitors, and antimetabolites. 96 MDR is a phenomenon that focuses on showing resistance to a number of anticancer drugs, which are functionally and structurally different from the initial chemotherapies used in the management of cancer. This is because of a number of sensitive tumors do respond to therapy in the initial stages, but later exhibit resistance.…”

Cell Migration Related to MDR—Another Impediment to Effective Chemotherapy?

“…All ABC proteins found in eukaryotic organisms are exporters; however, some ABC importers are present in prokaryotes. Among all 48 members of seven families of the human ABC proteins (ABCA–ABCG), members of three (ABCB, ABCC and ABCG) are involved in the active efflux of anticancer drugs from the cell cytoplasm [ 1 , 5 , 6 , 7 ]. They are also known by alternative names: Multi Drug Resistance protein 1 (MDR1) or P-glycoprotein (P-gp)—ABCB1; Multidrug Resistance Proteins (MRPs)—ABCC family; and Breast Cancer Resistance Protein/MitoXantrone Resistance-associated protein (BCRP or MXR)—ABCG2 [ 5 , 8 ].…”