Block 4 -- Pharmacogenetics & Pharmacogenomics Flashcards
(34 cards)
Define ideal drug.
One that is safe and effective
What percentage of DNA encodes all diversity?
0.1%
What are uses of genetics/genomics?
1) observations = new drugs (bench-bedside-bench)
2) diagnosis & prognosis
3) Choice of drug, dose, prediction of ADRs
4) monitoring of drug resistance
5) profiling infection & cancer
6) gene & stem cell therapy
What does SNP stand for?
single nucleotide polymorphism
Define polymorphism.
Mutation occurring at a frequency of >1% in a specific population
What is a synonymous polymorphism?
a point mutation encoding for the same amino acid
What is a nonsynonymous polymorphism?
a point mutation encoding for a different amino acid
What are types of SNPs?
synonymous/nonsynonymous
insertion/delete
What is the most common mechanism of gene variation?
SNP
How are SNPs related to disease/altered response
only some SNPs are associated with disease/altered response
Define polygenic.
Owing to the functions of many genes
What diseases can benefit from pharmacogenetics?
1) many cancers: breast, prostate, AML
2) autoimmune diseases
3) Type II Diabetes
What therapies can benefit from pharmacogenetics?
1) ACE inhibitor response
2) beta-agonist response
3) anti-cholinergic response
What does the TYMS gene encode?
Thymidylate synthetase
Describe the TYMS polymorphism.
- 28 bp tandem repeat
- Varies from 2 to 9 copies
- TS expression (3>2) = tumor resistance
How is resistance to 5-FU therapy assayed?
PharmacogenETICS
– TYMS gene (*3 > *2)
How does 5-FU work as an anti-neoplastic agent?
- 5-FU anabolism in target tissue –> 5F-dUMP
- - 5F-dUMP inhibits thymidylate synthetase
How many CYP450 isoforms are there?
57
What is the most studied CYP450 isoform?
CYP2D6
What are substrates for CYP450?
1) TCAs
2) Codeine
3) DM
4) Tamoxifen
What implications occur with no CYP2D6?
1) high risk for ADRs
2) No response from prodrugs
What are implications for CYP2D6 ultrametabolizers?
No drug response at ordinary dosage
Describe the metabolism of tamoxifen.
CYP2D6, CYP3A4, UGT2B7, UGT1A4
– UGT = glucuronidase
Active form: endoxifen/4-OH-Tam
How is pharmacogenetics related to aminoglycoside
Determines presence of 12S rRNA mutation that mimics ancestral form of ribosome
- Aminoglycoside attacks to cause ototoxicity
- this is a polymorphism!
