Pharmacogenomics part 1 Flashcards
define pharmacogenomics
the study of genetic factors that underline variation in drug responses
basically the study of how genes affect a person’s response to drugs
____ + _____ = pharmacogenomics
pharmacology + genomics
true or false
both endogenous and exogenous factors cause variations in drug response
true
name 3 ways in which there have been advances in pharmacogenomics
human genome project
advances in sequencing
GWAS (large genome wide associated studies)
what is an allele
one of 2 or more alternate forms of a gene.
arise by mutation. found at the same genetic locus
give an example of an allele
CYP2D6*3 is a important variant allele for the drug metabolizing enzyme CYP2D6
what is allele frequency
the fraction or percentage of times a specific allele is observed in proportion to the TOTAL OF ALL POSSIBLE ALLELES that could occur at a specific location on a chromosome
what is another name for polymorphism
variant
define polymorphism
any genetic variation in the DNA sequence
what is SNP
single nucleotide polymorphisms
base pair substitutions that occur in the genome
what is cSNP
coding single nucleotide polymorphism
base pair substitutions that occur in the CODING REGION
what are insertions/deletions
insertions or deletions of base pairs
may occur in coding or noncoding regions
true or false
insertions or deletions of base pairs always occur in the coding region
false - may be coding or non coding region
what are copy number variations
a segment of DNA in which a variable number of that segment has been found
what are PM, IM, EM, UM
they are different phenotypes that exist due to polymorphism
PM = poor metabolizer
IM = intermediate metabolizer
EM = extensive metabolizer
UM = ultra rapid metabolizer
what is haplotype
a series of alleles found in a linked locus on a chromosome
explain the relationship between glucose transporters and polymorphism
a mutation in glucose transporters that causes them not to work properly will cause glucose to not be transported into the cell and remain in the blood, causing HYPERGLYCEMIA
polymorphism is defined as variations with a prevalence of the minor allele of at least ___% in at least ____ population(s)
at least 1-2% in at least 1 population
name the 4 classes of DNA polymorphisms
which is most common?
RFLP - restriction fragment length polymorphisms
VNTR - variable number tandem repeats
STR - short tandem repeats (1-8 base pairs)
SNP - single nucleotide polymorphism (*** most common)
what are the benefits of pharmacogenomics?
there will be improved drug choices because you can predict who is likely to have a therapeutic response or experience an adverse effect based on genetics.
-appropriate dosing options
-improvement for drug development
-health care costs and harm to pts decrease
rank the following according to the relative dose of drug they will receive:
-extensive metabolizers
-intermediate metabolizers
-poor metaboliers
-ultrarapid metabolizers
will receive the most dose: ultrarapid metabolizers
extensive metabolizers
intermediate metabolizers
will receive least dose - POOR METABOLIZERS
Which type of metabolizer is the most common?
extensive metabolizer (then intermediate)
how many whole gene deletions exist for all the types of metabolizers
PM = ~0
IM = ~0.5
EM = 1-2
UM = greater than or equal to 2
phase 1 enzymes are involved in the biotransformation of over what % of prescription drugs?
over 75%
what may significantly affect drug levels in the blood?
polymorphisms in the phase 1 enzymes that metabolize over 75% of prescription drugs, like…
CYP2C19
CYP2D6
CYP2D6 metabolizes roughly _____% of all drugs
25%
name 4 classes of drugs that are metabolized by CYP2D6
beta blockers
antidepressants
antipsychotics
opioids
the gene for what enzyme is highly polymorphic, with about 100 alleles?
how many of these alleles are important?
gene for CYP2D6
9 are important
which CYP2D6 alleles are nonfunctional?
*3, *4, *5, *6
which CYP2D6 alleles have REDUCED function?
*10, *17, *41
which CYP2D6 alleles are fully functional?
*1, *2
which CYP2D6 allele is found in europeans at 20% frequency, but almost absent in asians at less than 1% frequency?
*4
which enzyme isoform is responsible for the metabolism of codeine/morphine
CYP2D6
Explain the phase 1 metabolism of codeine
metabolized by CYP2D6 via O-Demethylation into MORPHINE, which is 200x more potent than codeine.
this morphine binds to the micro Opioid receptor to produce analgesic activity
what is the significance of the fact that codeine is metabolized by CYP2D6 and some people may be ultra rapid/intermediate/extensive/poor metabolizers via this enzyme due to polymorphism?
poor and intermediate metabolizers will not get sufficient pain relief bc codeine is not being metabolized into the 200x more potent analgesic: morphine
poor metabolizers should receive an alternative agent like morphine or a non-opioid
intermediate metabolizers should receive the standard dosing but be closely monitored, and alternatives may be used
extensive metabolizers will receive the standard dosing
ultra metabolizers have an increases rink of side effects like drowsiness and respiratory depression. alternate agents should be used
which CYP isoform metabolizes acidic drugs?
name 4 classes of acidic drugs
CYP2C19
proton pump inhibitors
antidepressants
anti-epileptics
anti-platelet agents
how many major alleles of CYP2C19 are there?
name them
4
*2 and *3 are non function
*1 is fully functional
*17 has increased function
what class is fluoxetine
SSRI antidepressant
selective serotonin reuptake inhibitor
what is the name of the device that can check for 31 variations in 2 genes?
what 2 genes are they?
CYP2D6 and CYP2C19
AMPLICHIP - drop of blood obtained from inside the patient’s cheek
polymorphic phase 2 enzymes may cause what?
may diminish drug elimination and increase the risk for toxicities
phase 2 enzymes biotransformation reactions typically do what?
CONJUGATE endogenous molecules like sulfuric acid, glucuronic acid, and acetic acid onto a wide variety of substrates
so they can be eliminated
phase 2 reactions are primarily which enzymes
TRANSFERASES
a deficiency in glucose-6-phosphate dehydrogenase will cause what?
(G6PDH)
hemolytic anemia
what enzyme is part of the first and rate limiting step in the pentose phosphate pathway?
G6PDH
explain what G6PDH is important for
GSH and NADPH generation (imp for metabolism)
imp in RBC detoxification of ROS
protects hemoglobin oxidation
the gene for G6PDh is located on what chromosome
X chromosome (female)
the G6PDH gene is highly polymorphic with over ____ variants
180
___ females and ______ males show reduced G6PDH activity
homozygous deficient females and hemizygous (gene where one of its pairs is deleted) deficient males
how many WHO classes of G6PDH deficiency are there?
5
1 and 2 are severe deficiency
3 is moderate deficiency
4 is no deficiency (normal)
V has ENHANCED G6PDH activity, which is also bad
