Phase II Metabolism: (Conjugation Reactions)
general results of phase 2 conjugations
increase water solubility
2 reactions in phase 2 that dont follow general results
Phase II: Possible Conjugations
Glucuronic acid Conjugation
Conjugation with amino acids
Conjugation with CoA
Glucuronidation of Morphine:
__-Glu = more potent than morphine
__-Glu = antagonist
Major/most common route for phase II
Glucuronic Acid Conjugation
Glucuronic Acid Conjugation Accounts for major share of conjugates in urine/bile. why?
Good supply of glucuronic acid in liver
Many functional groups can conjugate
Glucuronidation Common Functional Groups are
Glucuronidation reaction involves:
1.Uridine-5'-Diphosphate-a-D-Glucuronic acid (UDPGA)
2.Binds to the Functional Group
3.Using the enzyme: UDP-Glucuronosyl Transferase (UGT)
Activation of Glucuronic Acid for Transfer
glucose 1-phosphate + UTP------> UDPGA
enzyme: UDPDG dehydrogenase
which type of glucuronidation involves the formation of an ester and is very reactive
Less Common Glucuronidations:
Quaternary ammonium glucuronides
what is unique about C-glucuronides
The H is acidic that the glucuronic acid is binding to
since Acyl Glucuronide forms an ester what tends to happen?
-migration from C1 to C2(occurs by tranesterification)
potential result of forming a hapten during acyl glucuronide
massive immune response might occur
Concentration of Glucuronides in Urine & Hydrolysis: what happens with Benzidine?
Some glucuronides get cleaved in the urine and return back to the parent form which is a carcinogen and causes bladder cancer
_____ and ______ are in Endoplasmic Reticulum
UDPGT and CYPs
Are all compounds conjugated w/ glucuronic acid are removed by kidneys?
Some endogenous ones excreted into intestinal tract w/ bile(__________)
__________ in _________ hydrolyzes the glucuronide conjugate back to the drug (for reabsorption into portal circ.)
beta-glucuronidase in intestinal flora
Steps in Enterohepatic Recycling of Glucuronides and consequences?
1. secretion in bile(intestine)
2. hydrolysis by beta-glucuronidase
3. reabsorption into portal circulation
Very lengthy action from recycled drugs!!
Sulfate Conjugation (Sulfation) by _________
Sulfate Conjugation (Sulfation) substrates:
Endogenous: steroids, neurotransmitters, bile acids, thyroxine,
Xenobiotics: phenolic drugs
unique feature of sulfate conjugates?
almost totally ionized and very acidic and reactive
Conjugation with Amino Acids typically involves _______
Conjugation w/ CoA:
What does CoA do?
What are the potential problems with CoA conjugates?
1. activates things for transfer( STILL ACTIVE)
2. makes another active cpd, can be transferred to something else for example a protein
acetylation primary substrates?
For acetylation what catalyzes transfer?
N-Acetyl Transferase (NAT)
what happens during acetylation
Decreases polarity of substrate, but substrates can be to
Polymorphism of NAT
Fast and slow acetylators: have SNPs on their NATs
Glutathione Conjugation substrates
Glutathione (GSH)= tripeptide of glycine, cysteine, and glutamic acid
1. Drugs can conjugate to GSH through __ atom, conjugates generally excreted in bile/urine
2. They can then be transformed to ___________( more soluble)
2. mercapturic acid derivatives
mechanism of Glutathione S Transferase (GST)
increases ionization of thiol in GSH
increases its nucleophilicity towards potentially harmful electrophiles, which then react with GSH
Important in detoxification
Reacting and being destroyed to keep other more important parts of the cell safe
Glutathione Conjugation sample substrates
alpha-beta unsaturated carbonyl groups
- Michael addition
GSH is found in high concentrations in the _________
1. generally _________, some drugs
2. ____ is methyl donor
1. endogenous substances