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difference between mutation and polymorphism?
occurs in less than 1% of population: mutation
more than 1% : polymorphism
what percent of the population has an increased risk of adverse drug reaction?
40%
non synonymous (missense) vs synonymous (sense)
non synonymous (missense): AA substitution
synonymous (sense): no AA change
where in a gene would a mutation most likely alter a protein?
in the exon
what does a mutation near the exon/intron border do?
change the number of exons
what does a mutation near the promoter/enhancer do?
alter cis/trans acting elements
what does a mutation in the intergenic region do?
unlikely to affect protein sequence, may alter 3º structure
compare three methods of DNA prep:
whole blood: high quality
buccal epithelial cells: low yield
whole saliva: high percent non human DNA
describe the Sanger assay
includes ddNTP for DNA chain terminator
describe microarray
determines genotype in terms of 2 CYP enzymes
describe taqman
fluorescent nucleic acid probe to detect and quantify specific PCR products
what was the first FDA approved pharmacogenetic test?
Clopidogrel is ____ by _____
list polymorphisms and their effect
is activated by CYP 2 C19
1 is WT
2 and 3 are not active- cause no therapeutic effect
17 is increased function
Warfarin is ____ by _____
list polymorphisms and their effect
metabolized by CYP 2 C9
1- WT
2 and 3 are less active: need to decrease dose because less clearance, increased bleeding risk
Warfarin normally ____ VKORC1
what would a polymorphism in VKOR do?
normally inhibits
polymorphism would increase sensitivity because less enzyme is present a lower dose of warfarin is needed
Tamoxifen + Codeine are ____ by _____
list polymorphisms and their effect
activated by CYP 2D6
(tam is prodrug)
1+2 are WT
3-6 are not active
9-41 have a decreased function
3-41 dont have same effect as WT
Tacrolimus + Cyclosporine are ____ by _____
list polymorphisms and their effect
metabolized by CYP 3A5
1 is WT
3,6,7 are not active
poor tacrolimus metabolism → organ rejection
5-FU is ____ by _____
list polymorphisms and their effect
metabolized by DPD
1,5,9 are WT
2,13 not active- TOXIC BUILDUP RISK
Azathioprine (immunosupp) is ____ by _____
list polymorphisms and their effect
activated to 6MP and metabolized to 6MMP (inactive) by TPMT
1 is WT
2,3,4 are not active: can cause dangerous build up and bone marrow tox
Irinotecan (chemo) is ____ by _____
list polymorphisms and their effect
activated to SN38 by carboxylesterases and metabolized by UDP-Glucuronosyl transferase 1A1
1- WT
6,28- not active
Isoniazid (TB antibiotic) is ____ by _____
list polymorphisms and their effect
metabolized by NAT2
4 IS WT
5-14 is less active, tox build up
what enzyme protects hemoglobin from oxidation and is a source of NADPH in RBCs
G6PD
what drugs create reactive species and should not be combined with ____ polymorphisms
G6PD polymorphisms react w
rasburicase in cancer patients
aspirin and sulfa agents
give 2 types of transporters
P glycoprotein and breast cancer resistance protein (BCRP)
what gene snp causes drug hypersensitivity?
HLA-B
what gene snp causes upregulation of virus immune response in HCV?
IFNL3
DNA mutagenesis initiation involves which types of mutations
point and frameshift
what aids in DNA repair?
alkyl transferases
Compare cancer development promotion and progression stages
promotion: reversible
no direct DNA change, alters gene expression
promoting agents: DES, BPA, dioxin
progression: irreversible
malignant cell population, complex gene alterations
progressor agents: arsenic, asbestos, benzene
what does dioxin do?
induces CYP 450 and increases oxidative stress
What do heterocyclic amines do
become covalently bound to DNA
what does arsenic do
multiple actions: inhibits DNA repair
what does asbestos do?
cell transcription and ROS
three endocrine disruptor mechanisms?
mimicry, blocking, epigenetic
what was the first endocrine disruptor?
DES
why are endocrine disruptors a public health issue?
-age: early exposure
-latency: early exposure has effects later in life
-dose response: dont act through linear response, low dose can have large effect
- epigenomic changes
differentiate plant defense mechanisms:
spines
thorns
prickles
trichomes
spines: modified leaves
thorns: modified branches/stems
prickles: extension of cortex
trichomes: originate from only epidermis (hard, sticky, fragile)
what is the largest plant toxin family
alkaloid
what are alkaloids made of and examples of alkaloids
amine/amino acid derived and have nitrogen containing base
atropine, cocaine, morphine, nicotine, muscarine
what is the most important medical plant toxin family
glycosides
what is a glycoside and examples
upon hydrolysis get sugar and nonsugar
cardiac glycoside (digoxin), cyanogenic glycosides (amygdalin in fruit seeds/pits)
what is a terpene vs terpenoid and example
derived from isoprene. terpene is hydrocarbon and terpenoid has an additional group
geraniol, limonene, linalool
what is a phenol and example
derived from phenols or phenyl + propyl linker
acetylsalicylic acid, methyl salicylate, capsaicin
Wolfsbane/Aconitine:
mechanism:
symptoms:
mech: prolonged activated of voltage gated Na channels. Acts on neurotoxin binding site 2
symptoms: cardiac arrhythmias is the usual cause of death
Yew Trees/ Taxines
mechanism:
symptoms:
mechanism: blocks L type voltage dependent Ca channels
symptoms: circulatory collapse, dec BP
Cardiac glycosides/digoxin
mechanism:
symptoms:
mechanism: inhibits Na/K/ATPase
increases Na and Ca
symptoms: cardiac arrhythmias is cause of death
Strychnine
mechanism:
symptoms:
mechanism: competitive antagonist for glycine neurotransmitter
symptoms: no muscle relax, painful dramatic symptoms
the lambeth poisoner used what toxin?
strychnine
Poison hemlock/Coniine
mechanism:
symptoms:
mechanism: nicotinic receptor agonist
symptoms: paralysis of diaphragm causes death
(no CNS)
Curare/D-tubocurarine + Rocuronium
mechanism:
symptoms:
mechanism: nicotinic antagonist
symptoms: paralytic agent
Atropine (nightshade)
mechanism:
symptoms:
mechanism: muscarinic antagonist
symptoms: dilation, bradycardia, muscarine antidote
Scopolamine (nightshade)
mechanism:
symptoms:
mechanism: muscarinic antagonist, crosses BBB
symptoms: motion sickness, dec oral secretions
what toxin is used in witches flying ointment
scopolamine
Physostigmine (calabar bean) + organophosphates
mechanism:
symptoms:
mechanism: ACh-esterase inhibitor
symptoms: respiratory paralysis
Cocaine
mechanism:
symptoms:
mechanism: indirect sympathetic stimulation: blocks NE and dopamine uptake
symptoms: local anesthetic and vasoconstrictor during surgery
Ephedrine (Ma Huang shrub)
mechanism:
symptoms:
mechanism: release of NE from nerve endings
symptoms: pseudoephed as decongestant
Quinine (Cinchona tree)
mechanism:
symptoms:
mechanism: interferes with parasites ability to digest hemoglobin, Na channel blocker
symptoms: treat malaria, tonic
vinka alkaloids + taxol
mechanism:
uses:
mechanism: prevents mitotic spindle division
uses: cancers
Salicylic Acid (willow trees)
mechanism:
uses:
mechanism: covalently binds COX 1+2 and inhibits PG
uses: analgesia, antipyretic, anti inflamm
Morphine
mechanism:
uses:
mechanism:inhibition at relay neurons in spinal cord
uses: acute and chronic , death due to respiratory
Capsaicin
mechanism:
uses:
mechanism: activates TRPV1 channels in nociceptors
uses: desensitizes, pain relief
give some fungal infection examples
athletes foot, tinea
C. neoformans: lung infection in immunocompromised
histoplasmosis: serious symptoms in immunocompromised
where does mycotox come from and give some mycotoxin mechanism examples
aflatoxin:
ochratoxin A:
ergot:
food molds (cereals, nuts, spices)
aflatoxins: damage liver, DNA
ochratoxin A: kidneys, oxidative damage
ergotism: St Anthony’s fire. Causes gangrenous and convulsions
give two examples of ergot alkaloid derivatives
LSD, anti migraine
give some mushroom toxin/alkaloids mechanisms
muscimol:
Psilocybin:
Mescaline:
Death Cap mushroom:
muscimol: GABA agonist
Psilocybin: 5HT2A agonist
Mescaline: 5HT2A agonist
Death Cap mushroom: RNA pol II inhibitor, inhibits mRNA synthesis
3 stage of death cap toxicity
1) GI
2) stop GI
3) hepatic necrosis, renal dys, death x
Note
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