Lecture 11- Phase II metabolism 1

Question 2

what is the enzyme used for glucurondation reaction?

Answer 2

UDP-GT

Question 3

What is the enzyme used for sulfation reaction?

Answer 3

Sulfotranserase

Question 4

give 6 conjugation reactions?

Answer 4

• glucuronidation
• sulfation
• amino acid conjugation
• methylation
• acetylation

Question 5

give the phase 1 metabolism reactions

Answer 5

• oxidation
• reducation
• hydrolysis

Question 6

give the phase 2 metbaolism reactions

Answer 6

conjugation

Question 7

Conjugation reactions.
-compounds have ______ molecular weight and are _____ water soluble
-_____ able to pass through cell membranes
-______ to excrete

Answer 7

-greater, more

• Less
• easier

Question 8

what does phase 2 metbaolism usually result in?

Answer 8

detoxification

Question 9

what is the most widely used phase 2 metabolism?

Answer 9

glucuronidation

Question 10

where are UDP-GTs found?

Answer 10

only in endoplasmic ret (luminal face)

Question 11

why is it beneficial for the cell to have the main
phase II enzymes in the same subcellular location as the main phase
I enzymes?

Answer 11

keeping them close speeds up metbaolism and improves drug clearence

Question 12

give an example of a glucoronide with biologicla actiity ?

Answer 12

morphine glucuronide

Question 13

Acyl glucuronides can be _______ → They bind to proteins and may cause ______ _____

Answer 13

harmful
immune reactions

Question 14

Two families: UGT1 and UGT2
At least ____ different UGT1 isoforms but all products of the ____
gene

Answer 14

10 same

Question 15

Glucuronide conjugates of MW ____ than 400 tend to be excreted in the bile wherases those ____ 400 are mainly excreted in urine

Answer 15

greater

smaller

Question 16

where might glucuronides excreted in bile undergo?

Answer 16

enterhepatic recirculation

Question 17

explain sulfotransferases

Answer 17

cytosolic enzymes that help the body remove drugs and hormones by adding a sulfate group (-SO₃) to them. This makes them more water-soluble so they can be easily excreted in urine

Question 18

give examples of endogenous substrates for sulfotransferases

Answer 18

-idothyronines, catecholamines and steroids

Question 19

give the 3 SLUT isoforms

Answer 19

SULT1A1
SULT1A3
SULT1C2

Question 20

SULTs use ___ as a source of sulfate

Answer 20

PAPs

Question 21

when a drug undergoes sulfation it forms a ___

Answer 21

sulfate ester (R-OSO3-) - making the drug higly water soluble so the body can easiliy excrete it in urine

Question 22

sulfation adds a ____ charge

Answer 22

• negative
  this stops the drug from interacting with its target - making it inactive
  dopamine sulfate has no biological activity but doparmine does

Question 23

what happens if a drug is too quickely sulfated ?

Answer 23

• becomes inactive before reaching its target - less active drug is available in the bloodstream - reducing its effect

Question 24

give quick paracetamol sulphation reaction

Answer 24

paracetamol > sulfotransferase> paracetamol sulfate

Question 25

READ

Answer 25

Many compounds may be conjugated by either sulfation or glucuronidation. Sulfation tends to be important at low substrate concentrations due to sulfate availability being limited

Question 26

give an example of a drug that needs sulfation for activity

Answer 26

Minoxidil (regaine) - used in the treatment of baldness and hypertension

Question 27

Some sulfoxy derivatives of pro-carcinogens are unstable and spontaneously form reactive ____ _______

Answer 27

nitrenium compounds

Question 28

which slut does Activation of N- hydroxyacetylaminofluorene need?

Answer 28

SLUT1A1

Question 29

explain the difference in mice and humans with SLUT stuff

Answer 29

Some toxic chemicals (AhR ligands like dioxins) are processed by SULTs to help remove them. - In mice, these chemicals reduce SULT activity, but in humans, this doesn’t seem to happen. = Toxins can affect SULT enzymes, but their impact is different in animals and humans

Question 30

what is one of the first conjugation reactions to be discobvered but the elast understood ?

Answer 30

amino acid conjugation

Question 31

the name hippuric acid suggests discovery of this pathway in which species of mammals?

Answer 31

horses

Question 32

history of amino acid conjugation

Answer 32

In 1841, Alexander Ure demonstrated that exogenous benzoic acid was metabolised to hippuric acid (confirmed by Keller in 1845) Requirement for carboxylic acid group – relatively few compounds are conjugated by this route.

Question 33

where is amino acid conjugation happens?

Answer 33

mitochondria

Question 34

what are the major conjugating amino acids in humans ?

Answer 34

- glycine , taurine and glutamine

Question 35

what is the initial reaction usually carried out by ?

Answer 35

- mitochondrial xendobiotic medium chain fatty acid : CoA ligases (MACS)

Question 36

describe the three steps in AAC

Answer 36

🔹 Step 1: Special enzymes (MACS) in the mitochondria activate the drug. 🔹 Step 2: Another enzyme (Glycine N-acyltransferase) attaches glycine to the drug. 🔹 Step 3: The modified drug becomes water-soluble and is excreted in urine.

Question 37

explain the bezoic acid conjugation

Answer 37

benzoic acid > (MACS) Benzoyl-CoA > (Acyl-CoA: glycine N-aceyltransferase ) Hippuric acid

Question 38

explain conjugation of salicylate

Answer 38

Salicylic acid >(ATP +CoA)> Salicyl-CoA> (Glycine) > Salicyluric acid

Question 39

why are so few xenobiotics conjugated to amino acids ?

Answer 39

- many xenobiotics are substrates for MACS but Not all of them end up being conjugated with an amino acid. \ MACS enzymes convert xenobiotics into CoA thioesters N-acyltransferase decides which ones get conjugated to amino acids Issue: This enzyme is very selective, so not all activated xenobiotics get conjugated.

Question 40

example of easiy conjugated and not conjugated well from amino acid reaction

Answer 40

✔ Salicyl CoA (from aspirin) → Easily conjugated and excreted. ❌ Methylenecyclopropylacetyl CoA (from hypoglycin, a toxic compound) → Not conjugated well, causing CoA depletion (which can be harmful)