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

Roy U, Barber P, Tse-Dinh YC, Batrakova EV, Mondal D, Nair M - Front Microbiol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Centre for Personalized Nanomedicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University Miami, FL, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the role of MRP efflux transporters in HIV-1 and TB therapy.
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Figure 1: Schematic representation of the role of MRP efflux transporters in HIV-1 and TB therapy.

Mentions: Multi-drug resistant proteins are part of the ABC superfamily of proteins that play an important role in the defense of cells against a wide range of xenobiotics. This family comprises a broad range of proteins found in organisms from bacteria to humans, and transport structurally diverse substances, such as ions, amino acids, sugars, peptides, and proteins across biological membranes. These drug efflux transporters have been implicated in the development of multi-drug resistance (MDR) (Figure 1). Cells selected for resistance to a cytotoxic drug may become cross resistant to a variety of drugs with different structures and cellular targets. MDR was thought to result exclusively from increase in P-gp activity encoded by the human MDR1 gene. However, researchers discovered that several cell lines selected for resistance did not show an increase in P-gp, yet became resistant to a range of natural product drugs (Zaman et al., 1994). In one of these non-P-gp MDR lines, the H69AR small cell lung carcinoma line found amplification and increased expression of a novel gene, the MRP (Cole et al., 1992). The overexpression of MRP has since been observed in several cell lines. Moreover, the subcellular location of MRP did not seem to be similar to that of a plasma membrane transporter, such as P-gp. This 190 KDa protein was found mainly in the endoplasmic reticulum rather than in the plasma membrane (Zaman et al., 1994). The discovery of MRP1 facilitated the discovery of eight more genes within the MRP family of which at least six (MRP2, MRP3, MRP4, MRP5, MRP6, and MRP8) are potentially involved in mediating drug resistance (Leslie et al., 2005). Noteworthy, breast cancer resistance protein (BCRP)—a transporter of the ABC superfamily—also acts to defend against toxins and xenobiotics by facilitating the excretion and limiting the absorption of potentially toxic substrate molecules. Known sites of BCRP expression include, the gut, bile canaliculi, placenta, testis, and brain (Natarajan et al., 2012).


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

Roy U, Barber P, Tse-Dinh YC, Batrakova EV, Mondal D, Nair M - Front Microbiol (2015)

Schematic representation of the role of MRP efflux transporters in HIV-1 and TB therapy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585023&req=5

Figure 1: Schematic representation of the role of MRP efflux transporters in HIV-1 and TB therapy.
Mentions: Multi-drug resistant proteins are part of the ABC superfamily of proteins that play an important role in the defense of cells against a wide range of xenobiotics. This family comprises a broad range of proteins found in organisms from bacteria to humans, and transport structurally diverse substances, such as ions, amino acids, sugars, peptides, and proteins across biological membranes. These drug efflux transporters have been implicated in the development of multi-drug resistance (MDR) (Figure 1). Cells selected for resistance to a cytotoxic drug may become cross resistant to a variety of drugs with different structures and cellular targets. MDR was thought to result exclusively from increase in P-gp activity encoded by the human MDR1 gene. However, researchers discovered that several cell lines selected for resistance did not show an increase in P-gp, yet became resistant to a range of natural product drugs (Zaman et al., 1994). In one of these non-P-gp MDR lines, the H69AR small cell lung carcinoma line found amplification and increased expression of a novel gene, the MRP (Cole et al., 1992). The overexpression of MRP has since been observed in several cell lines. Moreover, the subcellular location of MRP did not seem to be similar to that of a plasma membrane transporter, such as P-gp. This 190 KDa protein was found mainly in the endoplasmic reticulum rather than in the plasma membrane (Zaman et al., 1994). The discovery of MRP1 facilitated the discovery of eight more genes within the MRP family of which at least six (MRP2, MRP3, MRP4, MRP5, MRP6, and MRP8) are potentially involved in mediating drug resistance (Leslie et al., 2005). Noteworthy, breast cancer resistance protein (BCRP)—a transporter of the ABC superfamily—also acts to defend against toxins and xenobiotics by facilitating the excretion and limiting the absorption of potentially toxic substrate molecules. Known sites of BCRP expression include, the gut, bile canaliculi, placenta, testis, and brain (Natarajan et al., 2012).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Centre for Personalized Nanomedicine, Institute of NeuroImmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University Miami, FL, USA.

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.

No MeSH data available.


Related in: MedlinePlus