Lecture 11- Phase II metabolism 1 Flashcards
what is the enzyme used for glucurondation reaction?
UDP-GT
What is the enzyme used for sulfation reaction?
Sulfotranserase
give 6 conjugation reactions?
- glucuronidation
- sulfation
- amino acid conjugation
- methylation
- acetylation
give the phase 1 metabolism reactions
- oxidation
- reducation
- hydrolysis
give the phase 2 metbaolism reactions
conjugation
Conjugation reactions.
-compounds have ______ molecular weight and are _____ water soluble
-_____ able to pass through cell membranes
-______ to excrete
-greater, more
- Less
- easier
what does phase 2 metbaolism usually result in?
detoxification
what is the most widely used phase 2 metabolism?
glucuronidation
where are UDP-GTs found?
only in endoplasmic ret (luminal face)
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?
keeping them close speeds up metbaolism and improves drug clearence
give an example of a glucoronide with biologicla actiity ?
morphine glucuronide
Acyl glucuronides can be _______ → They bind to proteins and may cause ______ _____
harmful
immune reactions
Two families: UGT1 and UGT2
At least ____ different UGT1 isoforms but all products of the ____
gene
10 same
Glucuronide conjugates of MW ____ than 400 tend to be excreted in the bile wherases those ____ 400 are mainly excreted in urine
greater
smaller
where might glucuronides excreted in bile undergo?
enterhepatic recirculation
explain sulfotransferases
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
give examples of endogenous substrates for sulfotransferases
-idothyronines, catecholamines and steroids
give the 3 SLUT isoforms
SULT1A1
SULT1A3
SULT1C2
SULTs use ___ as a source of sulfate
PAPs
when a drug undergoes sulfation it forms a ___
sulfate ester (R-OSO3-) - making the drug higly water soluble so the body can easiliy excrete it in urine
sulfation adds a ____ charge
- negative
this stops the drug from interacting with its target - making it inactive
dopamine sulfate has no biological activity but doparmine does
what happens if a drug is too quickely sulfated ?
- becomes inactive before reaching its target - less active drug is available in the bloodstream - reducing its effect
give quick paracetamol sulphation reaction
paracetamol > sulfotransferase> paracetamol sulfate
READ
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
give an example of a drug that needs sulfation for activity
Minoxidil (regaine)
- used in the treatment of baldness and hypertension
Some sulfoxy derivatives of pro-carcinogens are
unstable and spontaneously form reactive
____ _______
nitrenium compounds
which slut does Activation of N-
hydroxyacetylaminofluorene need?
SLUT1A1
explain the difference in mice and humans with SLUT stuff
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
what is one of the first conjugation reactions to be discobvered but the elast understood ?
amino acid conjugation
the name hippuric acid suggests discovery of
this pathway in which species of mammals?
horses
history of amino acid conjugation
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.
where is amino acid conjugation happens?
mitochondria
what are the major conjugating amino acids in humans ?
- glycine , taurine and glutamine
what is the initial reaction usually carried out by ?
- mitochondrial xendobiotic medium chain fatty acid : CoA ligases (MACS)
describe the three steps in AAC
🔹 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.
explain the bezoic acid conjugation
benzoic acid > (MACS) Benzoyl-CoA > (Acyl-CoA: glycine N-aceyltransferase ) Hippuric acid
explain conjugation of salicylate
Salicylic acid >(ATP +CoA)> Salicyl-CoA> (Glycine) > Salicyluric acid
why are so few xenobiotics conjugated to amino acids ?
- 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.
example of easiy conjugated and not conjugated well from amino acid reaction
✔ 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)
