Phase II Metabolism: (Conjugation Reactions)

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general results of phase 2 conjugations

increase water solubility
increase excretion

2 reactions in phase 2 that dont follow general results

methylation, acetylation

Phase II: Possible Conjugations

Glucuronic acid Conjugation
Sulfate Conjugation
Glutathione Conjugation
Conjugation with amino acids
Conjugation with CoA
Acetylation
Methylation

Glucuronidation of Morphine:

__-Glu = more potent than morphine
__-Glu = antagonist

6
3

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

Phenols, Alcohols
Thiols
Amines
Carboxylic acid

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
cofactor: 2NAD

which type of glucuronidation involves the formation of an ester and is very reactive

Acyl glucuronidation

Less Common Glucuronidations:

Quaternary ammonium glucuronides
C-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)
- Haptens

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?

NO

Glucuronides:
Some endogenous ones excreted into intestinal tract w/ bile(__________)

enterohepatic cycling

Glucuronides:
__________ 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 _________

Sulfotransferase (SULT)

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 _______

glycine

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?

aromatic amines

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

Glutathione Conjugation:
1. Drugs can conjugate to GSH through __ atom, conjugates generally excreted in bile/urine

2. They can then be transformed to ___________( more soluble)

1.S
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
Suicide mechanism
Reacting and being destroyed to keep other more important parts of the cell safe

Glutathione Conjugation sample substrates

electrophilic carbons
alpha-beta unsaturated carbonyl groups
- Michael addition

GSH is found in high concentrations in the _________

liver

Methylation:
1. generally _________, some drugs
2. ____ is methyl donor

1. endogenous substances
2. SAM

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