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.
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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.
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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.
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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.
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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.
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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.
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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.
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