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#drug efflux

3 public questions tagged with this topic.

Membrane Transportation

The MDR1 (ABCB1) transporter is responsible for:

MDR1 officially ABCB1, also called P-glycoprotein P-gp, is a 1280 amino acid 170 kDa glycosylated plasma membrane exporter noted for conferring resistance to colchicine and doxorubicin in selection experiments. Tissue distribution includes apical brush border of small intestinal enterocytes limiting drug absorption, canalicular membrane of hepatocytes promoting biliary excretion, luminal membrane of proximal renal tubule mediating urinary elimination, endothelial cells of blood-brain barrier restricting central entry, and placental syncytiotrophoblast protecting fetus. Substrates are typically neutral or cationic amphipathic molecules of 300 to 2000 Da that partition into lipid bilayer such as paclitaxel, vincristine, etoposide, imatinib and cyclosporine. Transport cycle involves two ATP hydrolysis events: ATP binding closes NBD dimer, induces outward-facing TMD conformation collapsing high-affinity pocket and expelling substrate, then hydrolysis resets system. Genomic amplification and pregnane X receptor mediated induction after chemotherapy increase efflux, lowering cytosolic concentration and causing therapy failure requiring dose escalation and combination strategies. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Sharom, Pharmacogenomics 2008, P-glycoprotein; Alberts, 7th ed., Chapter 11 MDR transporters.

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Membrane Transportation

Which transporter is involved in multidrug resistance (MDR)?

Multidrug resistance in oncology frequently originates from increased efflux reducing intracellular drug accumulation below cytotoxic threshold. ATP-binding cassette transporters, particularly ABCB1 P-glycoprotein, ABCC1 MRP1 and ABCG2 BCRP, are major contributors. They are primary active pumps using two ATP hydrolysis events per cycle to switch transmembrane domains from high-affinity inward-facing to low-affinity outward-facing state, literally vacuuming hydrophobic substrates from inner membrane leaflet. Their drug-binding pocket is large, flexible and polyspecific, accommodating anthracyclines, vinca alkaloids, taxanes, epipodophyllotoxins, tyrosine kinase inhibitors and immunosuppressants despite distinct structures. Physiologically these transporters localize at intestine, liver canaliculus, kidney tubule, blood-brain barrier and placenta providing xenobiotic protection. Overexpression after chemotherapy through gene amplification or transcriptional activation via pregnane X receptor leads to cross-resistance to many drugs, alters pharmacokinetics of orally administered compounds, and motivates development of third-generation inhibitors like tariquidar, though clinical success remains limited by toxicity and compensatory mechanisms. Such detailed mechanistic insight is frequently examined in competitive tests including NEET, CUET, CSIR-NET and GATE where transporter classification, energetics and disease linkage are integrated into problem-solving questions.

Ref: Gottesman et al., Nat Rev Cancer 2002, Multidrug resistance; Ambudkar et al., Annu Rev Pharmacol 1999.

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Microbial Physiology

Which resistance mechanism allows bacteria to pump antibiotics out of the cell?

Efflux-mediated resistance represents highly efficient active extrusion mechanism driven by transmembrane energy gradients. Bacterial multidrug efflux systems belong to five major families: resistance-nodulation-division RND such as AcrAB-TolC tripartite pump in Escherichia coli and MexAB-OprM in Pseudomonas aeruginosa, major facilitator superfamily MFS such as TetA for tetracycline, multidrug and toxic compound extrusion MATE, small multidrug resistance SMR and ATP-binding cassette ABC transporters using ATP hydrolysis rather than proton motive force. These pumps capture antibiotics from periplasmic space or cytoplasmic leaflet and use proton antiport or ATP hydrolysis to export them to extracellular medium, continuously lowering intracellular concentration below inhibitory threshold required for target binding. Overexpression via mutations in local repressors like marR, acrR, mexR or activation of global stress regulators marA, soxS, ramA increases pump copy number and broadens substrate range, conferring cross-resistance to dyes, detergents, bile salts and chemically unrelated antibiotic classes. Unlike enzymatic inactivation that destroys drug chemically, or target site modification via methylation or point mutation that reduces binding affinity, or plasmid transfer that describes gene movement mechanism, efflux physically pumps drug out, exemplifying intrinsic and acquired multidrug resistance especially prominent in Gram-negative pathogens and biofilm-associated tolerant states.

Ref: Lodish et al., Molecular Cell Biology, 8th ed., Chapter 15: Bacterial Efflux Pumps and Drug Resistance.

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