PSC2002/L11 ABC Transporters & Multidrug Resistance Flashcards
What is MRP?
Multidrug resistance-associated protein
MW190kDa
Describe MRP function and expression. (2)
12 known
Functions including protection, xenobiotics to channeling ions
Facilitate extrusion of numerous glutathione, glucoronate and sulfate conjugates
Expressed in numerous tissues of the body (ubiquitous)
Describe the structure of MRP1. (3)
17 transmembrane helices forming a pore
2 highly conserved NBDs
Extracellular loops connecting transmembrane helices
Describe the history of MRP1.
First member of MRP family to be identified by studies on drug-resistant cell line showing presence of a transporter which is not PGP
Describe the expression of MRP1. (3)
Encoded by ABCC1 (chromosome 16)
Main MRP member contributing to MDR
Expressed at high levels in tissues including brain, testis and lungs, low in liver
Preference for amphiphilic organic anions
Describe LTC4.
Physiological high affinity substrate
Family of lipid mediators of inflammation synthesised from arachidonic acid
How is LTC4 formed?
Conjugation of GSH to LTA4 through reaction catalysed by leukotriene synthase enzyme (in eosinophils, monocytes, neutrophils, macrophages)
How does MRP1 affect LTC4?
MRP1 mediates transport of LTC4 across plasma membrane
What is formation of LTC4 important in?
Asthma and allergy (in lung)
What is phase I metabolism mediated by and what reactions are involved?
Mediated by cytochrome P450 enzymes
Oxidation
Reduction
Hydrolysis
What are phase II metabolism reactions?
Conjugation
With glutathione, amino acids
Methylation
Glucorinidation
Acetylation
Sulfation
What are phase III metabolism reactions?
Drug transport
Describe movement of glutathione through membranes.
Through MRP1 using GSH as cotransporter
E.g., for vincristine
Give 2 examples of MRp1 substrates.
Xenobiotics
Antibiotics
Antifolate
Antimalarial
Anthracenedione
Anthracycline
Camptothecin
Vinca alkaloids
Endobiotics
Glucorinide conjugates
Sulfate conjuagtes
Folates
Peptides
Describe effects in MRP1 KO mice. (3)
No significant difference in viability or fertility
Elevated tissue GSH
Unchanged tissue glutathione in organs expressing little/no MRP1 (e.e., liver, small intestine)
MRP1 dispensable for development and growth
Increased sensitivity to several chemotherapies
What is the role of MRP1 in neuroblastoma?
MRP1 direct downstream target of MYCN
Describe the relationship between MYCN and ABC transporters. (2)
MYCN directly regulates expression of MRP1
MYCN regulates expression of a range of ABC transporters
MDR1 is a target of MYCN
What is the role of MRP2?
Glucuronide transporter
High level of expression on bile canaliculus of hepatocyte & apical membranes of kidney and intestine
Contribution to drug glucuronide elimination in bile
Elimination of bilirubin in body
What is the role of MRP2 in haem metabolism?
MRP2 transports bilirubin from liver into bile
Describe Dubin-Johnson Syndrome. (2)
No active MRP2 due to mutations
High bilirubin levels of bilirubin glucuronide in their plasma
Usually benign condition but may see jaundice in pregnancy or with some drugs
What family of transmembrane conductors foes CFTR belong to?
Atypical member of ABCC family
Short ABCC protein with only 2 MSD (membrane spanning domain)
Describe the role of ABCC8/SUR1.
SUlphonylurea receptor important in control of blood glucose by pancreas
No transport role
Acts as ATP-sensitive regulator of potassium channel
How do sulfonylureas cause increased insulin secretion?
Sulfonylureas bind to receptor causing effect on K+(KATP) channel
Membrane potential becomes more positive
Opens voltage-gated Ca2+ channels
Rise in intracellular calcium leads to increased insulin secretion
