Transporters II Flashcards
What does ABC stand for?
ATP-Binding Cassette
What are ABC transporters made of?
multiple subunits that include transmembrane proteins and membrane-associated ATPases
What do all ATPase subunits need to translocate substrates across membranes?
Energy from hydrolysis in of ATP
ABC transporters are considered to be an ABC superfamily based on _______?
molecular homology of the sequence and organization of their ABC domains
What is the role of ABC uptake transporters?
Shuttle a variety of nutrients for cell health
What is the role of ABC efflux transporters?
Shuttle lipids, sterols, drugs, etc primarily as a detoxication mechanism
How many ABC genes are there (currently) in humans?
48 ABC genes
How were ABC transporters first identified?
Due to their roles in their drug resistance
What are the four core proteins of the ABC transporters?
Two trans-membrane subunits (alternate between inwards and outwards facing orientation and two cytosolic subunits
Why does the structure of the transmembrane domains matter?
Because the structure dictates specificity (what the transporters will transport)
What causes the conformational change in the nucleotide and what does it do?
Binding of substrate to the transmembrane domains; allows 2 ATP molecules to bind
What is the Vacuum cleaner mechanism?
Closing of outer “open” conformation → Substrate gets fully internalized to the transport pore → Opening of the inner side of the transporter → Substrate gets sucked into the cell
What are the three most studied and relevant ABC exporters in pharmacology?
P-glycoprotein (P-gp/ABCB1), Multidrug resistance-associated protein 1 (MRP1/ABCC1), and Breast cancer resistance protein (BCRP/ABCG2)
What are the four main nomenclatures in the ABC transporter family and what is their function?
ABCA, ABCB, ABCC, ABCG; transports drugs
What does OATPs stand for?
Organic Anion Transporters
What are OATPs?
Na⁺-independent facilitated transporters that facilitate the flux of large amphipathic organic anions and neutral/cationic drugs
What are some examples of large amphipathic organic anions and neutral/cationic drugs?
Statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensive, and anti-cancer drugs
How many recognizable subfamilies do mammalian OATPs have?
Five recognizable subfamilies
What are the proteins relevant to pharmacology?
OATP2B1 (statins, ACE inhibitors, Angiotensin Receptor blockers, antibiotics, antihistamines, antihypertensives, and anticancer drugs) and OATP1B1 and OATP1B3 (anti-cancer drugs of the kinase inhibitor family)
What is the mechanism of transport for OATPs?
Facilitated transporters that do not use ATP
What are the two general mechanisms for OATPs?
Countercurrent exchange of one anion in, with another anion out, Countercurrent exchange of two anions - two in, two out
What are Organic Cation Transporters (OCTs)?
Members of the solute carrier (SLC) superfamily that work to eliminate endogenous small organic cations as well as many drugs in the liver, kidney, and intestine
What are mutations/deficiencies of OCTs associated with?
Diseases such as gout (hyperuricemia), carnitine (important amino acid) deficiency, Wilms tumors, adrenocortical carcinoma, and lung, ovarian, and breast cancer
What is the role of OCT1 (SLC22A1)?
Disposition and hepatic clearance of mostly cationic drugs and endogenous compounds. It works with MATE1 (in the liver sinusoids; blood side) to facilitate biliary elimination of OCT1 substrates direct to the intestine. It is required for the uptake of the drug metformin in cells
Where can you find OCT1 (SLC22A1)?
Liver and brain
What is the role of OCT1 (SLC22A1)?
Functions together with other transporters called MATE1 and MATE2-K in the kidney to eliminate OCT2 substrates into the urine. The important drug substrates under this include metformin (antidiabetic), cisplatin and oxaliplatin (chemotherapy) lamivudine (anti-HIV)
Where can you find OCT2 (SLC22A2)?
Human kidney tubules
What happens with the natural transport activity in OCT3 (SLC22A3)?
Psychoactive drugs (Molly, E, PCP, amphetamine, methamphetamine and cocaine) inhibit the transport of serotonin and dopamine
What happens when psychoactive drugs inhibit the homeostasis of histamine, serotonin, and dopamine?
Upsets the brain chemistry in the mood/reward centers, and so leading to addiction (person has to take in more and more of the drug so that they feel “happy”)
What causes the drug-drug interactions for OCT3 for kidney elimination?
Alters pharmacokinetics
Explain what happens in the drug-drug interaction in OCT3
Drugs compete for the kidney, and cimetidine (anti-ulcer drug) “wins” and inhibits the clearance of the other drugs. This causes higher levels of drugs in the same dose as well as drug-drug interaction. Higher level of drugs in the systems could be fatal as it can cause adverse drug reactions
What are the two mechanisms of OTPs?
ATP independent and Facilitated diffusion, countercurrent exchange (ion gradient is the driving force)
What is the influx mechanism for OTPs?
Electrogenic facilitated diffusion, which is the nonspecific flux of cationic solutes. This mechanism is opportunistic, meaning it is not a continuous catalytic cycle (mechanism in kidney tubules)
What is the efflux mechanism in OTPs?
Counter exchange of substrate for H+ ions (mechanism in the kidney)
What is the importance of the influx and efflux mechanisms?
Keeps balance of the electrolytes in the body
