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PHAR 202 > Transporters II > Flashcards

Transporters II Flashcards

1
Q

What does ABC stand for?

A

ATP-Binding Cassette

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2
Q

What are ABC transporters made of?

A

multiple subunits that include transmembrane proteins and membrane-associated ATPases

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3
Q

What do all ATPase subunits need to translocate substrates across membranes?

A

Energy from hydrolysis in of ATP

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4
Q

ABC transporters are considered to be an ABC superfamily based on _______?

A

molecular homology of the sequence and organization of their ABC domains

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5
Q

What is the role of ABC uptake transporters?

A

Shuttle a variety of nutrients for cell health

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6
Q

What is the role of ABC efflux transporters?

A

Shuttle lipids, sterols, drugs, etc primarily as a detoxication mechanism

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7
Q

How many ABC genes are there (currently) in humans?

A

48 ABC genes

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8
Q

How were ABC transporters first identified?

A

Due to their roles in their drug resistance

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9
Q

What are the four core proteins of the ABC transporters?

A

Two trans-membrane subunits (alternate between inwards and outwards facing orientation and two cytosolic subunits

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10
Q

Why does the structure of the transmembrane domains matter?

A

Because the structure dictates specificity (what the transporters will transport)

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11
Q

What causes the conformational change in the nucleotide and what does it do?

A

Binding of substrate to the transmembrane domains; allows 2 ATP molecules to bind

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12
Q

What is the Vacuum cleaner mechanism?

A

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

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13
Q

What are the three most studied and relevant ABC exporters in pharmacology?

A

P-glycoprotein (P-gp/ABCB1), Multidrug resistance-associated protein 1 (MRP1/ABCC1), and Breast cancer resistance protein (BCRP/ABCG2)

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14
Q

What are the four main nomenclatures in the ABC transporter family and what is their function?

A

ABCA, ABCB, ABCC, ABCG; transports drugs

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15
Q

What does OATPs stand for?

A

Organic Anion Transporters

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16
Q

What are OATPs?

A

Na⁺-independent facilitated transporters that facilitate the flux of large amphipathic organic anions and neutral/cationic drugs

17
Q

What are some examples of large amphipathic organic anions and neutral/cationic drugs?

A

Statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensive, and anti-cancer drugs

18
Q

How many recognizable subfamilies do mammalian OATPs have?

A

Five recognizable subfamilies

19
Q

What are the proteins relevant to pharmacology?

A

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)

20
Q

What is the mechanism of transport for OATPs?

A

Facilitated transporters that do not use ATP

21
Q

What are the two general mechanisms for OATPs?

A

Countercurrent exchange of one anion in, with another anion out, Countercurrent exchange of two anions - two in, two out

22
Q

What are Organic Cation Transporters (OCTs)?

A

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

23
Q

What are mutations/deficiencies of OCTs associated with?

A

Diseases such as gout (hyperuricemia), carnitine (important amino acid) deficiency, Wilms tumors, adrenocortical carcinoma, and lung, ovarian, and breast cancer

24
Q

What is the role of OCT1 (SLC22A1)?

A

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

25
Q

Where can you find OCT1 (SLC22A1)?

A

Liver and brain

26
Q

What is the role of OCT1 (SLC22A1)?

A

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)

27
Q

Where can you find OCT2 (SLC22A2)?

A

Human kidney tubules

28
Q

What happens with the natural transport activity in OCT3 (SLC22A3)?

A

Psychoactive drugs (Molly, E, PCP, amphetamine, methamphetamine and cocaine) inhibit the transport of serotonin and dopamine

29
Q

What happens when psychoactive drugs inhibit the homeostasis of histamine, serotonin, and dopamine?

A

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”)

30
Q

What causes the drug-drug interactions for OCT3 for kidney elimination?

A

Alters pharmacokinetics

31
Q

Explain what happens in the drug-drug interaction in OCT3

A

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

32
Q

What are the two mechanisms of OTPs?

A

ATP independent and Facilitated diffusion, countercurrent exchange (ion gradient is the driving force)

33
Q

What is the influx mechanism for OTPs?

A

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)

34
Q

What is the efflux mechanism in OTPs?

A

Counter exchange of substrate for H+ ions (mechanism in the kidney)

35
Q

What is the importance of the influx and efflux mechanisms?

A

Keeps balance of the electrolytes in the body

PHAR 202 (8 decks)

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