W4 L4 - Transporters Flashcards
what are transporters and their function
Transporters are proteins localised within the membrane bilayer – “integral transmembrane proteins”
Function: translocation of substances across membranes
(i) Solute Carrier (SLC) transporters
(ii) ATP-Binding Cassette (ABC) transporters
overview of active/passive transport
Passive transport – down a concentration gradient.
Active transport (ATP) – against a concentration gradient.
where are nutrients absorbed
- in the intestine, aided by enzymes and transporters
- Large macromolecules (proteins, complex carbohydrates) can not be absorbed
- Enzymes brake down macromolecules into smaller, absorbable molecules.
Carbohydrate digestion
Sucrase: sucrose —> glucose + fructose
Lactase: lactose —> glucose + galactose
Maltase: maltose —> glucose + glucose
Glucose uptake in the intestine
Intestine:
- Glucose is absorbed by the Na+-dependent glucose transporter-1 SGLT1 or SLC5A1
- Glucose uptake is energised by movement of Na+ ions down their electrochemical gradient into the enterocyte.
- SGLT1/SLC5A1 possesses 14 membrane-spanning regions.
what are proteins digested to
small peptides & amino acids
how are small peptides transported into the cell
- digested into small peptides & amino acids
- Small peptides transported into cell by PepT1/SLC15A1 transporter
- Peptide uptake is energised by movement of H+ down their electrochemical gradient into the enterocyte.
- PepT1/SLC15A1 possesses 12 membrane-spanning regions
Absorption via SLC transporters
- Transporters is extremely efficient
- Exploited by drug designers
- Design drugs based on natural products, e.g. peptide-based drugs (PepT1)
PepT1 substrates
- Antibiotics (e.g. ampicillin, cefixime, cefadroxil)
- Angiotensin-converting enzyme (ACE) inhibitors (e.g. captopril, enalapril)
- Valacyclovir (prodrug of acyclovir) and valganciclorvir (prodrug of ganciclorvir)
Prodrugs are the parent drugs with valine attached
OATP1B1 Transporter
- Organic Anion Transporting Polypeptide (OATP)1B1/SLCO1B1
- OATP1B1 involved in the uptake of statins
- Statins inhibit liver HMG-CoA reductase
Inhibition reduces cholesterol synthesis in the liver
Indication: reduce plasma cholesterol level
ABC Transporters
- Whilst some SLC transporters aid drug absorption, some ABC transporters may hinder absorption
- ATP Binding Cassette (ABC) transporters hydrolyse ATP to energise transport of substrates against a concentration gradient
- Usually transport substrates out of cells (efflux)
- P-glycoprotein (P-gp) / ABCB1
- Breast Cancer Resistance Protein (BCRP) / ABCG2
Efflux transporter
work via an energy-dependent mechanism (active transport) to pump out unwanted toxic substances through specific efflux pumps
P-glycoprotein / ABCB1 structure
- 2 Transmembrane domains (TMDs), each consisting of 6 helices
- 2 Nucleotide-binding domains (NBDs) in cytoplasmic region (intracellular facing) that hydrolyse ATP.
- Forms a pore in the membrane
BCRP / ABCG2 structure
- 1 Transmembrane domain (TMD), consisting of 6 helices
- 1 Nucleotide-binding domain (NBD) in cytoplasmic region (intracellular facing) that hydrolyses ATP.
- Two ABCG2 proteins combine
- Form a pore in the membrane
ABC Transporters
- ABCB1 and ABCG2 – expressed in the apical membrane of intestinal enterocytes.
- Can reduce absorption of therapeutic drugs
- many anti-cancer drugs are ABCB1 substrates
- Drugs from many therapeutic classes are substrates of ABC transporters. examples - immunosuppressants, antibiotic, cardiotonic)
- Some drugs can inhibit P-glycoprotein / ABCB1 activity
This reduces the amount of drug substrate the transporter can efflux out of the cell - ABCG2 also transports therapeutic drugs
What’s the problem with anti-cancer drugs being ABCB1 substrates
- they are pumped out if drug was taken orally so IV line has to be used for cancer patients for example
Problem with inhibiting efflux pumps
- drug not pumped back into the intestine so more reaches blood
- increases conc of drug in blood which could lead to toxicity however, pharmacokinetic effect is increased
Doxorubicin (anti-cancer drug) Extravasation
- leaking out of fluid from blood vessel
- drug leaks out and kills surrounding tissue
