pharmacogenetics and pharmacogenomics DSA Flashcards
what are the 3 main phenotypes that can result from pharmacogenetic changes in phase 1 enzymes
normal metabolizers
poor metabolizers
ultrafast metabolizers
what is the significance of the allele 28 (UGT1A1-28) in terms of camptothecin toxicity …
camptothecin is a therapeutic for cancer and it has a metabolite (7-ethyl-10-hydroxycamptothecin)
this metabolite inhibits DNA topoisomerase that is needed for DNA replication (so it helps with cancer that is out of control) BUT often toxicity can occur if there is too much of this metabolite
UGT1A1 encodes for a enzyme that glucuronidates the metabolite of camptothecin–> so it can then be excreted in the bile
if there is an allele change such as with allele 28 then this reduces the transcription of the enzyme that helps with toxicity
what is the problem with slow acetylators who are taking Isoniazid for Tuberculosis therapy…
decrease in N-acetyltransferase —> at risk for drug-induced systemic lupus erythematous like syndrome
what is the significance of the BCHE gene
what does it encode for
what is its products function
what is the allele that is abnormal and what is the outcome of this abnormal allele
BCHE gene encodes for butyrylcholiesterase
this hydrolyzes succinylcholine and reduces the amount that can reach motor end plates (succ is a nicotinic agonist that causes paralysis)
A allele - abnormal
enzyme produced by the A-allele has reduced activity and the patient is unable to degrade succ at the normal rate–> prolonged muscle paralysis
what is the pathogenesis of G6PD deficiency
Product of G6PD reaction is NADPH (source of reducing equivalents in the red blood cell)
NADPH –> protects the cell against oxidative damage by regenerating reduced glutathione from its oxidized form
In the deficiency→ oxidant drugs such as primaquine deplete the cell of reduced glutathione → leads to hemolysis due to oxidative damage to red cells
what does warfarin do…
warfarin blocks the enzyme Vit K epoxide reductase complex I (encoded by VKORC1 gene)→ reduce vit K so it can be recycled and used in coagulation factor biosynthesis
what are the two allelic changes that affect warfarin therapy and what are the outcomes …
o Warfarin metabolite
• Undergoes phase I detox by CYP2C9. Pt’s with deficiency in CYP2C9 genes on average require a 20 % lower dose
o Abnormal VKORC1 enzyme (target of warfarin)
• 2 major haplotype families (A and B) → differ in dose of warfarin needed
• A/A→ 3.2
• B/B → 6.1
• A/B→ 4.4
• B haplotype → 3-fold increase in the levels of mRNA for VKORC1 gene→ more enzyme made→ more Warfarin is needed in order to achieve the same degree of blockage of Vitamin K recycling
• A haplotype→ require less Warfarin
• Asian patients are more sensitive to lower doses of warfarin
