Lecture 16 - Introduction to Pharmacogentics Flashcards
What is Pharmacogenetics?
The study of variations in drug response
between individuals that have a hereditary
basis
how common are genetic polymorphisms? And what can they be?
> 1%
- can be base substitution (SNP single nucleotide polymorphism ) insertion or deletion
how often do polymorphisms occur?
every 1 in 1000 bases (most dont have a functional effect
describe functional polymorphisms?
- effect on biological activity
- often due to amino acid substitution , splice site change or effect on transcription factor binding
compare phenotyping vs genotyping
pheno
- measure enzyme activity directly - giving a probe drug and measuring metabolites or direct enzyme assay (EXAMPLE - on red or white blood cells)
geno
- look directly for presence of mutation in induviduals DNA (need to know gene responsible for defect + what mutation to screen for)
Describe CYP2D6
9 exons
metabolism of 1/4 all drugs
highly polymorphic
>100* alleles reported
location on chromosome 22 22q13.2 ( the long arm (q), region 1, band 3, sub-band 2.)
what are the classic methods historically used to assess the activity of the CYP2D6 enzyme
Sparteine phenotyping Debrisoquine phenotyping
(Based on how well a person metabolizes a probe drug (debrisoquine or sparteine), you can infer CYP2D6 enzyme activity.)
describe allele *3 mutation type, molecular effect and BstNI Digestion
mutation type
-Frameshift (exon 5)
molecular effect
-Deletion of A → loss of function
BstNI Digestion
-Alters restriction site → changed pattern
describe allele *4 mutation type, molecular effect and BstNI Digestion
mutation type
-Splice site (intron 3/exon 4)
molecular effect
-G→A substitution → splicing error
BstNI Digestion
-Destroys BstNI site → altered pattern
describe allele *5 mutation type, molecular effect and BstNI Digestion
mutation type
-Whole gene deletion
molecular effect
-No CYP2D6 gene present
BstNI Digestion
-No PCR product → nothing to digest
what phenotype and enzyme activity does 0–1 copies of functional alleles show?
Phenotype
Poor/Intermediate Metabolizer
Enzyme Activity
Low or no enzyme
what phenotype and enzyme activity does 2 copies of functional alleles show?
Normal (Extensive) Metabolizer
Normal activity
what phenotype and enzyme activity does >3 copies of functional alleles show?
Ultrarapid Metabolizer
High enzyme activity
what are the drugs affected by ultra metabolisers CYP2D6?
Codeine → converted to morphine by CYP2D6.
➜ UMs can produce too much morphine, leading to toxicity.
Antidepressants (e.g., fluoxetine, nortriptyline)
➜ UMs may metabolize these too quickly, making them less effective.
Beta blockers, tamoxifen, tramadol, and others.
what is the most common allele of PMs found in 20% of europeans?
*4
_% of Europeans have very fast
metabolism (UMs)
1
PMs vs UMs
PMs- Failure to metabolise drugs/active metabolites and greater risk of toxicity
* Inability to activate prodrugs
UMs-
Poor response to certain antidepressants due to fast metabolism
* May suffer toxicity to prodrugs
describe CYP2D6 and codien
codiene - opiate prodrug
- metabolism of codien to morphine dependent on CYP2D6
what happens with UMs and codiene? what are the risk?
- coverts codien to morphine too quickely - high morphine levels
risks
- children- severe resperiatry dissress / death
- breast feeding mothers - high morphine in breast milk - danger to baby PG 16 on regulations
read pg 17
What is NAT2?
An enzyme that acetylates (modifies) drugs and chemicals (xenobiotics)
-Found on chromosome 8p22
-Important for drugs like isoniazid (TB treatment)
induvials with normal NAT2 activity are _____ acetylators
fast
- 50% of europeans lack NAT2 activity - slow acetylators (TWO MUTATED COPIES OF THE GENE)
How is nat2 activity tested?
penotyping
- test drug (caffine) measure metabolites
genotyping
- look for NAT2 gene varients in DNA
describe isoniazid treatment
- slow acetylators are more likely to have increased risk of hepatotoxicity
- fast acetylators more likely to show poor response to intermittent dosing
describe hydralazine therapy
- slow acetylators - increased risk of developing autoimmune systemic lupus
describe the global variation in acetylator phenotype
NAT25 50% of europeans but <5% east aisians
NAT27 20% of east asians but <5% european /africans
