23. Drug Action on Transporters Flashcards
How do molecules cross the membrane?
Diffusion and active transport
Explain diffusion.
Diffusion - movement of a substance from an area of high concentration to low concentration.
* doesn’t require energy
* best suitable for neutral charged compounds
* facilitated diffusion requires protein
Explain active transport.
Active transport - movement of a substance from an area of low to high concentration.
* requires energy (direct or indirect)
* primary active transport - directly uses ATP for energy
* secondary - uses energy from other molecules moving with their electrochemical gradient
Describe the difference between active transport and facilitated diffusion.
- Both active transport and facilitated diffusion require proteins.
- Facilitated diffusion moves a molecule from high to low concentration
- Active transport moves a molecule from low to high concentration
- Active transport requires energy
Explain the mechanism of galactoside permease.
Galactoside Permease is a secondary active transporter for lactose.
* energy from ATP is used to create a concentration gradient, in this case –> H+ from the proton pump.
* the energy for lactose transport comes from the H+ gradient
Describe the difference between uptake and efflux transporters.
Uptake/reuptake transporter - movement into intracellular matrix
Efflux tranporter - movement into extracellular matrix
What are the two broad classes of transporters?
ABC transporters - ATP-binding cassette transporters
SLC transporters - solute carrier proteins
Describe ABC transporters.
- usually exist as a dimer
- transmembrane domain (TMD) consists of alpha helices (12) embedded in the membrane bilayer
- intracellular loop (ICL)
- the ABC (ATP binding cassette) domain in the cytoplasm binds ATP and a substrate
What happens when there is hydrolysis of ATP on an ABC transporter?
Hydrolysis of ATP –> conformational change –> moves the substrate against its concentration gradient
* ABC transporters can only export substrates as efflux transporters
Explain the function of ABC transporters. What can their use lead to?
Function: to remove drugs from cell –> lowering the intracellular drug concentration
* their activity can lead to multidrug resistance
Describe the mechanism of efflux of substrates.
- Substrate binds ot intracellular side of transmembrane domain
- ATP binding changes the conformation of the protein.
- Substrate is secreted into extracellular space.
- ATP hydrolysis.
- ADP release restores protein to open dimer conformation
Explain what P-glycoprotein: ABCB1 is.
- AKA MDR1 - most well known ABC transporter
- Expressed in intestinal epithelium, hepatocytes, renal proximal tubular cells, and blood-brain barrier
- MDR1 is an ATP-dependent efflux pump with broad spectrum specificity
Explain the mechanism of P-glycoprotein: ABCB1
- The presence of foreign substances is detected my nuclear receptors
- Drug binds to the receptor –> increases transcription of P-gp, removes drug from cell
- ABC transporters are often drug efflux pumps that impact the ability of drugs to engage their targets
Explain the relation between P-glycoprotein and cancer drug resistance.
Cancer cells express high levels of p-glycoprotein.
* P- glycoprotein effluxes anti-cancer drugs out of cancer cells –> result: drug resistance
* once a patient is resistant to one type of chemotherapy –> much more likely to be resistant to other chemotherapies.
Relate the development of p-glycoproteins inhibitors and cancer drug resistance.
The development of p-glycoprotein inhibitors may reduce drug resistance in cancer cells and increase efficacy of anti-cancer drugs
* these MDR1 inhibitor drugs have consistently dissapointed in clinical trails –> dont know why
