Lecture 9 - Cytochromes P450 2 Flashcards
___-___% of drugs rely on P450 enzymes for metabolism
70-80
what are the 3 main P450 enzymes that 90% of drugs are just handled by?
CYP3A4 (metabolizes ~50% of all drugs)
CYP2D6
CYP2C9
what are the 3 stages of identification of specific p450 isoform responsible for metabolism of drug?
1.Correlation analysis using human liver microsome bank
2. inhibition studies
* Chemical inhibition. Specific chemical inhibitors for several isoforms
* Antibody inhibition. Specific antibodies that inhibit enzyme activity available
3. Studies using purified or expressed enzymes. Wide range now
available
what enzyme does warfarin and ibuprofen use?
CYP2C9
What enzyme does codeine /metoprolol use?
CYP2D6
What enzyme does nifedipine, cyclosporin use?
CYP3A4
how does CYP2D6 work?
- targets drugs with a nitrogen and hydrophobic part
- adds an oxygen 5-7 A away from the nitrogen to help break down drug
- 5-10% of people lack this enzyme
- not inducible
- cardiovascular agents antisychotics or antidepressants
give CYP2D6 substrates?
- cardiovascular agents
- psychoactive agents
- ## morphine derivatives
how does CYP2C9 work?
- areas of strong hydrogen bond forming /ion pair form 5 to 10 A from metabolism site
- NSAIDs
- some show low activity due to amino acid subs (genetic polymorphism )
- inducaible by BARBITURATES and rfampicin
CYP2C9 substrates
ibuprofen
NAPROXEN
THC
s- warfarin
phenytoin (epilep)
how does CYP3A4 work?
- highly inducible by glucocorticoids (RIFAMPICIN)
- structual diversity
- large binding site
- Common reactions: N-dealkylation & aromatic hydroxylation
- genetic differences have less impact than in other P450s
CYP3A4 substrates
- tamoxifen
- cocaine
- lidocaine
- verapamil
describe CYP2C19
- omeprzole + clopidogrel
- 3% of UK pop lack activvity due to genetic polymorphism
- inducible by rifampicin and BARBITUATES
What are the factors determining metabolism by specific P450 isoforms?
- topography of active site of enzyme
- degree of steric hindrance of access of FE-O complex to possible sites of metabolism in substrate
- ease of electron or hydrogen abstraction from various carbons or heteroatoms of the substrate
CYP1A1
Activates harmful chemicals (like polycyclic aromatic hydrocarbons, PAHs). Found outside the liver and increases when exposed to these substances.
CYP2E1
Breaks down alcohol (ethanol) and can speed up its own production (autoinduction).
CYP1A2
Processes caffeine and can turn some chemicals (arylamines) into carcinogens (cancer-causing).
