Lecture 8 Flashcards
1
Q
Phase II Biotransformation
A
- Conjugation reactions:
– Glucuronidation.
– Sulfation.
– Glutathione conjugation.
– Methylation.
– Acylation.
– Phosphate conjugation. - Requires a polar group.
- Enzymes located in ER (UDP-GT) or cytoplasm.
2
Q
Glucuronidation & Glucosidation
A
- Conjugation with glucuronic acid or glucose.
- Most important and common type of Phase II
biotransformation. - Reactive intermediates can be formed from glucose.
- High capacity, low affinity reactions.
- Ability to react with wide range of functional groups.
3
Q
Glucuronidation
A
- UDP-GTs are inducible.
- Subject to inter-individual variation.
- Products filtered into urine are efficiently excreted.
- Products excreted into bile are susceptible to enterohepatic
circulation:
– Intestinal flora have -glucuronidase activity.
– Glucuronides can be cleaved by acid or base.
– Cleaved aglycones can be reabsorbed.
4
Q
Sulfate Conjugation
A
- Biotransforms xenobiotics as well as endogenous compounds.
- Occurs in vertebrates, invertebrates, fungi, bacteria.
- High affinity and low capacity.
- Enzyme catalyzes the transfer of sulfonate, not sulfate (i.e., SO3-,
not SO4-). - Generally is a detoxification mechanism but has been implicated
in the formation of toxic intermediates.
5
Q
Acetylation
A
- Major route of biotransformation for xenobiotics with
aromatic amines (R-NH2) or a hydrazines (R-NH-NH2). - Cytosolic N-acetyltransferases:
– Present in liver and many other tissues.
– Wide species variability.
– Humans, rats, and hamsters express two N-acetyltransferases (NAT-1
and NAT-2).
– Fast and slow acetylation phenotypes in humans. - Can also have O-acetylation.
6
Q
Methylation
A
- Common but minor pathway.
- Makes substrates slightly less water soluble and masks
available functional groups for conjugation. - Wide variety of acceptor substrates:
– Proteins, lipids, phospholipids and nucleic acids.
– Xenobiotics.
– Metals.
7
Q
Glutathione Conjugation
A
- Substrates share physicochemical properties:
– Hydrophobic.
– Contain an electrophilic atom.
– React nonenzymatically with glutathione, but glutathione transferases
(GSTs) increase the rate of reaction. - Protective effect; concentration of glutathione is high (10 mM).
- Some GST substrates are also inducers.
- GSTs are major determinants of differential drug-induced toxicity.