EXAM 5 - Drug Metabolism 4 Flashcards
Explain what occurs at this step of the CYP450 catalytic mechanism.
Reduction of Fe3+ to Fe2+
* makes the configuration larger
* Fe2+ allows oxygen and CO to bind
Explain what occurs during this step of the CYP450 catalytic mechanism.
Oxygen binds directly to Fe2+
Explain what occurs during this step of the CYP450 catalytic mechanism.
- the first oxygen leaves as H2O
- second oxygen leaves as product (ROH)
- then Fe3+ heme group enters catalytic cycle again
Is arachidonic acid able to give multiple products or just one?
Arachidonic acid gives different products depending on the P450 enzyme that acts on it.
Explain why substrates can give different products based on the CYP450 enzyme.
The amino acids around the catalytic site are different depending on the P450 enzyme.
* this means that they can bind the substrate differently
* orient and bind to substrate to give different product
Explain why human CYP2A6 hydroxylates coumarin, while rat CYP2A1 epoxidates coumarin.
There are differences around the catalytic site.
Human CYP2A6
* Phe and Asn amino acids orient coumarin so that the C7 is closest to iron –> C7 gets hydroxlyzed
Rat CYP2A1
* The and Asn orients coumarin differently and makes coumarin get epoxidized
Explain what contribution the catalytic site size has to do with the product.
The large catalytic site of enzymes can possibly fit multiple substrates and give off multiple products.
Explain why enzymes can cause a lot of drug drug interactions?
Enzymes can be inhibited or induced by many other drugs.
Describe the CYP450 1 family.
CYP1A - important for envrionmental carcinogens
CYP1A2 - metabolizes acetaminophen
* inhibited by ciprofloxacin
* induced by smoking
Describe the CYP450 2 family.
- Metabolizes a lot of drugs
- Can be induced/inhibited by a lot of drugs
Describe CYP2D6.
Not inducible
* responsible for metabolism of a large number of important/common drugs.
Describe the CYP450 3 family.
CYP3A - most abundantly expressed CYP450s in the liver and intestine
CYP3A4 - strongly lipophilic
Describe the chemicals that are made toxic by CYP450 enzymes.
- CYP1A1
- CYP1A2
- CYP2A6
- CYP2B6
- CYP2C8, 9, 18, 19
- CYP2D6
- CYP2E1
- CYP3A4
- CYP4A9/11
What type of reactions are Phase 2 reactions?
Conjugation reactions.
Describe drug metabolism characteristics of Phase 2 enzymes.
- All require cofactors
- will result in large increase in water solubility (except methylation and acetylation)
- glucuronidation, sulfation, methylation, and acetylation: conjugation reaction between electrophilic cofactor and nucleophilic site on drug or xenobiotic.
- conjugation with amino acids or glutathione: reaction between nucleophilic cofactor and electrophilic site on drug or xenobiotic
Which of the Phase 2 enzymes metabolize the most drugs?
UGTs
