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Membrane transporters and drug response
- 2. Membrane Transporters andDrug Response
- 3. Introduction • Cell membrane– Barrier • Selectively permeable • Drug absorption, distribution, elimination • Specialized transport proteins
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- 9. Membrane Transport Proteins •Channels • Carriers
- 10. Channel Proteins • Passivetransport • Protein-lined passageways • Speed of transport • Signalling in Nervous system
- 11. • Drugs –Receptors • Nicotinic AcetylCholine Receptor
- 12. Selectivity of ionchannels • Size of central pore • Cations and anions • nAChr • K+ Leak channels
- 14. Gating of IonChannels • Regulation of opening of pore • Gating: Voltage Ligand Mechanical
- 18. Carrier Proteins • Actuallybinds to a specific molecule and physically carries it across the membrane via a conformational change • Energy may or may not be required • Slower than channels • Drugs – resemble endogenous ligands
- 19. Passive Carriers • Facilitatethe downhill transport of substances across membranes • No energy input • Glucose Transporters
- 20. Active Carriers • Transportof solutes against their gradients • Requires energy • 3 types: ATP-driven Ion Pumps Coupled transporters ABC transporters
- 21. ATP-Driven Ion Pumps •Utilize the energy liberated by ATP hydrolysis to move ions across membranes, against their gradients. • Na+-K+-ATPase Pump: 2 K+ in, 3 Na+ out
- 23. Coupled Transporters • Usethe energy stored in ion gradients to actively transport molecules across membranes • Secondary Active Transporters • 2 mechanisms: Symport Antiport
- 24. Symport • The carrierprotein transports two solutes in the same direction
- 25. Antiport • One iontraverses the membrane in one direction and another metabolite is transported in the other direction.
- 26. ABC Transporters • ATP-BindingCassette superfamily
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- 28. Family Member AliasExpression Function ABCA ABCA1 To ABCA12 Ubiquitous Removal of cholesterol and PLs onto HDL particles Drug resistance Surfactant protection ABCB ABCB1 to ABCB11 MDR1,PGP Ubiquitous Multidrug resistance Phosphatidylcholine transport Iron transport Bile salt transport ABCC ABCC1 to ABCC12 MRP Ubiquitous Drug resistance Organic anion transport Nucleoside transport Chloride ion transport Sulfonylurea receptor ABCD ABCD1 to ABCD4 ALD1,ALDR PMP70 Peroxisomes VLCFA transport regulation ABCE ABCE1 OABP Ovary, testes, spleen Oligoadenylate-binding protein ABCF ABCF1 ABCF2 ABCF3 ABC50 Ubiquitous ABCG ABCG1 ABCG2 ABCG4 ABCG5 ABCG8 Human white ABCP, MXR, BCRP Ubiquitous Cholesterol transport Drug resistance Sterol transport
- 29. GENE NAME NOOF FAMILY MEMBERS DISEASES ABCA 12 Tangier Disease, Stargardt Syndrome ABCB 11 Bare Lymphocyte Syndrome Type I, X Linked Sideroblastic Anemia with Ataxia ABCC 13 Dubin-Johnson Syndrome, Pseudo-Xanthoma, Cystic Fibrosis ABCD 4 Adrenoleukodystrophy ABCE 1 ABCF 3 ABCG 5 Sitosterolemia
- 30. P-Glycoprotein • Permeability glycoprotein/MDR1 • Intestinal epithelium, hepatocytes, renal proximal tubular cells, adrenal gland and capillary endothelial cells (BBB) • Pumps out hydrophobic substances
- 32. • Overexpressed inhuman cancer cells • Multi-drug Resistance • Transports a variety of substances with different chemical structures • Clinical trials: Drugs that inhibit P-gp used in the treatment of highly drug-resistant cancers
- 33. MRP • Multidrug Resistanceassociated Protein/ Canalicular Multispecific Organic Anion Transporter 1 (cMOAT) • Actions similar to P-gp • Functions in biliary transport
- 34. BCRP • Breast CancerResistance Protein • Mitoxantrone and Camptothecin analogues • Expressed in placenta • Enhances excretion of xenobiotics • Secretion of vitamins in human milk
- 35. SLC Transporters • 48families • Passive transport, Facilitated diffusion and Ion-channel transport • Transport of substrates In and Out of the cell • OATP, OCT, SGLT, MATE
- 36. OATP • Organic Anionsacross cell membrane • Endogenous substrates: Bile acids, Bilirubin, thyroid and steroid hormones • Drugs: Anti-cancer, Antibiotic, Lipid lowering agents, Anti-diabetic drugs, toxins and poisons
- 37. OCT • Organic Cationsacross cell membrane • Endogenous substrates: Na+ , Histamine, Dopamine, NE, Uric Acid • Drugs: Diuretics, Quinine, Choline, Cimetidine etc.
- 38. SGLT • Sodium GlucoseLinked Transporter • Renal Glucose reabsorption • SGLT 2 – Use in Diabetes
- 40. MATE • Multi-drug andToxin Extrusion protein • Bacteria – Cation transporters • Metformin, Cimetidine, Topotecan
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- 42. Pharmacokinetics • Absorption anddistribution or excretion • Protective barriers • ABC transporters BBB Other tissues
- 43. • Hepatic transporters: ABC SLC Supplementaryto Hepatic Enzymes • Renal Transporters: Mainly SLC – OATP, OCT
- 44. Pharmacodynamics • Clinical use:Drugs acting on brain • SLC 1 and 6 • GABA, Glutamate, MAO, NE, 5HT, Dopamine
- 45. Adverse Drug Response •Control exposure of cell to foreign substances • 3 categories • Decreased uptake or secretion • Enhanced uptake/reduced efflux • Inhibition by drug • Eg. Loperamide vs. Quinidine
- 46. Clinical Implications • Targetsfor drug action • Clinical studies focused on genetic variation in membrane transporters • Important in highly drug resistant cancers
- 47. Conclusion • Drug development •Lacunae in knowledge • Further studies
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