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.
Highlights
Specialty section: This article was submitted to Virology, a section of the journal Frontiers in Microbiology
Multi-Drug Resistance Proteins (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
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
Summary
These compounds are not known to conjugate with GSH This implies that GSH is necessary for a possible co-transport mechanism or plays a role as a cofactor for substrate transport. It seems that the transport efficiency is impacted by the hydrophobicity of the substrate. Drug transport may be impacted by the increased ATP binding and ATPase activity caused by GSH. GSH appears to be substrates for both MRP4 and MRP5 as well, but unlike other members of the MRP family, they transport cyclic nucleotides cAMP and cGMP and even antiretroviral drugs 9-(2-phosphonylmethoxyethyl) adenine, which is independent of GSH (Ballatori et al, 2005). The rank order of potency for MRP-related drug efflux transport was nelfinavir > ritonavir > sequinavir > amprenavir > indinavir (Bachmeier et al, 2005). Interaction between the HIV1 protease inhibitor, P-gp, and MRP drug efflux transporters has been reported, a quantitative assessment as to the extent of this interaction has not been performed, since this group of drugs is commonly utilized in combination with other HIV-1 protease inhibitor or various antiviral agents as part of a HAART regimen (Bachmeier et al, 2005)
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