7 pharmacogenomics

Question 1

What is pharmacogenomics?

Answer 1

study of how an individual’s genetic inheritance affects the manner in which they respond to drugs

Question 2

Are there polymorphisms in metabolic enzymes?

Answer 2

yes and the differences can cause toxicity, especially if both alleles are mutated

Question 3

P450 CYP 2D6

Answer 3

• metabolizes 20-25% of drugs
• highly polymorphic gene-inactive in 2-10%
• detected by modern pharmacogenetic methods (microarray and PCR)

drugs metabolized:

• tricyclic anti-depressants
• anti-arrhythmics
• beta blockers
• neuroleptics

Question 4

P450 CYP 2C9

Answer 4

• metabolizes 15% of all drugs
• 40% of pop het
• homo 1%
• accounts for 10% pop variability

drugs metabolized
-warfarin–>excessive bleeding and hemorrhage

Question 5

P450 CYP 2C19

Answer 5

• metabolizes 5% of all drugs
• common inactive allele: CYP2C19*2
• most common in asian pop

Drugs metabolized
ADRs:
Plavix-prodrug converted to active metabolite

Question 6

P450 CYP3A4

Answer 6

metabolizes 50% of drugs
*** No inactivating polymorphic variants

but contraindications

• grapefruit
• polyphenolic compounds-flavonoids, furanocomarins

Question 7

NAT2

Answer 7

phase 2 enzyme; found in liver

• inactivating polymorphisms-ineffective conjugation: slow acetylator phenotype
• 2 mutant alleles- 90% slow acetylator phenotype

Drugs associated

• isoniazid
• hydralazine
• sulfonamides

Question 8

What is polymorphism is warfarin affected by?

Answer 8

CYP2C9

gene: vit k epoxide reductase-which is the target of warfarin-variability render warfarin inactive

Question 9

What are some therapeutics based on recombinant properties?

Answer 9

hormone replacement

gene cloning-Epogen-