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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

Sequence Alignment of MRP2, MRP4, Rv0194 with ClustalW2. http://www.ebi.ac.uk/Tools/msa/clustalw2/.
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Figure 3: Sequence Alignment of MRP2, MRP4, Rv0194 with ClustalW2. http://www.ebi.ac.uk/Tools/msa/clustalw2/.

Mentions: There is a large number of putative efflux pumps (EP) encoded in the Mycobacterium tuberculosis genome belonging to multiple major transporter families including the ABC-type transporters that are homologous to human MRPs (Black et al., 2014). DrrA (Rv2936) gene has been associated with efflux of multiple drugs including RIF, isoniazid (INH), and ethambutol (EMB) (Black et al., 2014; Li et al., 2015). Overexpression of ABC EP system Rv1456c-Rv1457c-Rv1458c was found in clinical isolates that are resistant to at least one of the four first-line drugs RIF, EMB, INH, and streptomycin (STR) (Hao et al., 2011). Increased expression of ABC transporters Rv1217c-Rv1218c in MDR-TB has been correlated with higher minimum inhibition concentrations (MICs) for RIF, and the overexpression of Rv1218c was correlated with higher MICs for INH (Wang et al., 2013). Another ABC transporter found in M. tuberculosis, Rv0194, has also been associated with resistance to a variety of antibiotics including STR (Danilchanka et al., 2008). Sequence alignment of Rv0194 with human MRP2, MRP4 is shown in Figure 3.


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)

Sequence Alignment of MRP2, MRP4, Rv0194 with ClustalW2. http://www.ebi.ac.uk/Tools/msa/clustalw2/.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Sequence Alignment of MRP2, MRP4, Rv0194 with ClustalW2. http://www.ebi.ac.uk/Tools/msa/clustalw2/.
Mentions: There is a large number of putative efflux pumps (EP) encoded in the Mycobacterium tuberculosis genome belonging to multiple major transporter families including the ABC-type transporters that are homologous to human MRPs (Black et al., 2014). DrrA (Rv2936) gene has been associated with efflux of multiple drugs including RIF, isoniazid (INH), and ethambutol (EMB) (Black et al., 2014; Li et al., 2015). Overexpression of ABC EP system Rv1456c-Rv1457c-Rv1458c was found in clinical isolates that are resistant to at least one of the four first-line drugs RIF, EMB, INH, and streptomycin (STR) (Hao et al., 2011). Increased expression of ABC transporters Rv1217c-Rv1218c in MDR-TB has been correlated with higher minimum inhibition concentrations (MICs) for RIF, and the overexpression of Rv1218c was correlated with higher MICs for INH (Wang et al., 2013). Another ABC transporter found in M. tuberculosis, Rv0194, has also been associated with resistance to a variety of antibiotics including STR (Danilchanka et al., 2008). Sequence alignment of Rv0194 with human MRP2, MRP4 is shown in Figure 3.

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