Unit 1 - CYP Flashcards
what is the classification scheme for cytophrome P450?
CYP #-letter-# letter-letter # = family (>40% sequence-homology) letter = subfamily (>55% sequence-homology) # = isoenzyme letter-letter = allele
what is the overview of cytochromes?
preform RedOx reactions (phase 1)
- bound to lipid membranes of SER
- most are found in liver, but also in lung, kidney, heart, brain
what is the difference between induction and inhibition?
induction - biotransformation by induced CYP enzymes results in either increased activity of prodrugs, or enhanced elimination of drugs
inhibition - results in increased bioavility of a drug, or decreased activity of a prodrug
what are the 6 important CYPs?
1A2 2C9 2C19 2D6 2E1 3A4
what are major drugs that 1A2 acts on?
caffeine and theophyllin
what are major drugs that 2A6 acts on?
coumarin, nicotine
what are major drugs that 2C9 acts on?
phentoin, warfarin
what are major drugs that 2C19 acts on?
diazepam (vallium)
what are major drugs that 2D6 acts on?
codeine
what are major drugs that 2E1 acts on?
paracetamol
what are major drugs that 3A4 acts on?
terfenadine, verapamil
what are major inducers of 1A2?
smoking, charred food
what are major inducers of 2C9?
rifampicin (rifampin), St. John’s wort
what are major inducers of 2C19?
St. John’s wort
what are major inducers of 2D6?
Rifampin
what are major inducers of 3A4?
St. John’s wort
what are major inhibitors of 1A2?
grapefruit juice
what are major inhibitors of 2C9?
macrolides (antibiotics)
what are major inhibitors of 2C19?
fluoxetine (anti-depressant)
what are major inhibitors of 2D6?
quinidine, haloperidol (anti-psychotic)
what are major inhibitors of 3A4?
ketoconazole, itraconazole (antifungals)
when does CYP polymorphism occur? which ones have it?
biotransforming properties of an enzyme are altered, causing change in rate of activity
- occurs in 2C9, 2C19, and 2D6
- translation of DNA sequences into proteins results in phenotypic expression of genes
- if there is a mutation to DNA, polymorphism may exist
what kind of metabolizers are CYP 2C9 or 2C19 polymophisms?
poor metabolizers
- 9 has 1-3% in Africans, Asians, and whites
- 19 has 20% in Africans, 15-20% in Asians, and 3-5% in whites
what kind of metabolizers are CYP 2D6 polymorphisms?
both poor and extensive metabolizers poor -Africans 2-8% -Asians > 1% -Whites 5-10% extensive -Asians 1% -Ethiopians 30% -N. Europeans 1-2% -S. Europeans 10%
what happens if someone with a 2C9/2C19 polymorphism takes warfarin?
polymorphism means they are a poor metabolizer
-this means warfarin, in its active form, stays in the body and is toxic
what happens if someone with a 2D6 polymorphism takes codeine?
if they are a poor metabolizer, then codeine will build up and morphine will not be made (little effect)
if they are a strong metabolizer, then morphine will be converted in high amounts (large effect)
what happened when a girl took terfenadine (antihistamine) and ketoconazole (anti-fungal) together?
she got Torsades de Pointes
- the ketoconazole acted as an inhibitor to CYP 2A4, which should metabolize terfenadine
- since CYP 2A4 was inhibited, terfenadine built up, and caused cardiac toxicity
what happens if someone takes codeine with rifampin?
rifampin is an inducer of CYP 2D6, thus increasing metabolism of codeine to morphine
-this would cause increased morphine, or opiod toxidrome
what happens if someone takes verapamil and St. John’s wort?
SJW is an inducer of CYP 3A4
-verapamil would be metabolized to its inactive form much faster, thus there would be a decrease in efficacy
