LECTURE 9: TOXICOGENOMICS Flashcards
DIFFERENCES….
§ Adverse drug reactions impose a burden on health care systems account for
a significant morbidity, mortality and cost
§ Estimates that pharmacogenomics accounts for ~80% variability in drug
efficacy and safety
§ Over 400 genes are clinically relevant in drug metabolism, est’d~200 are
associated with ADR
TERMINOLOGY
Pharmacogenomics
Pharmacogenetics
Toxicogenomics/toxicogenetics
Pharmacogenomics
Characterization of the genome-wide response to small molecular molecules administered with therapeutic intent. Study of how interacting systems of genes determine individual drug responses.
“The right drug for the right disease”
Pharmacogenetics
Study of how variant forms of human genes contribute to inter-individual variability in
drug response. Single gene focus is at the level of the individual.
“The right drug for the right patient”
Toxicogenomics/toxicogenetics
Deals with adverse effects of toxins/poisons due to genetic differences of the
individual that impact the response.
CYP enzymes
you can have single gene effects where you can have an unstable enzyme where the enzymes doesnt work as well
Normal, majority of the population is responding as predicted.
Altered substrate specificity: Mutations are going to decrease that, but substrate specificity
you can have mutations that will result in an increase in activity. Increased metabolism, increase turnover, which is, gonna can cause problems with increasing toxic metabolites.
Example: CYP2C9
- CYP2C9, important member of CYP2C subfamily
1 is normal allelle
2 - intermediate allele
3 is no activity
– Accounts for ~18% of P450 protein content in human liver microsomes
– Catalyzes ~20-25% of clinically administered drugs currently on the
market
* Highly polymorphic, more than 60 variants
* Linked to impaired metabolism
– Phenytoin
– S-Warfarin
– Losartan
– NSAIDs
* Biggest problems:
– Poor metabolism – increased effects!
– Warfarin à bleeding out
Warfarin
Coumadin®
– Racemic mixture (50:50, R:S-warfarin)
– Anti-thrombotic agent
* S-warfarin 3-5x more potent than Rwarfarin
– Narrow therapeutic index agent
* Monitor INR
* Adverse event: bleeding
CYP2C91 Wild-type N/A Normal Normal
CYP2C92 C430T Arg144Cys Decrease Decrease
Example: CYP2C19
Mutations mostly lead to slow metabolizers
* Important drugs affected:
– S-mephenytoin
– Proton-pump inhibitors
– Diazepam
– Propanolol
– Imipramine
– Amitryptiline
– Clopidogrel
* ~7 mutations have been found to contribute to the well-characterized
CYP2C19 poor metabolizer
CYP-Dependent Metabolism of Clopidogrel
Absorption – Drug efflux transporter, P-glycoprotein (ABCB1)
* Metabolism – (CYP2C19, CYP3A)
* P2Y12 (receptor) and glycoprotein IIB/IIa (receptor) (platelet aggregation)
CYP2D6
Many genetic variation (~75 variants)
25 – 30% of clinically “key” medications
Four phenotype subpopulations of metabolizers
– Poor metabolizers (PM)
– Intermediate metabolizers (IM)
– Extensive metabolizers (EM)
– Ultrarapid metabolizers (UM)
- Poor metabolizers
Slower on average - Lower frequency of nonfunctional alleles
- Higher frequency of reduced activity alleles
CYP2D6
Codeine is a Substrate of CYP2D6
Prodrug Effects
Codeine metabolized to morphine:
CYP2D6 ultra-rapid metabolizers abdominal pain
CYP2D6 poor metabolizers no analgesia
CYP2D6 Poor metabolizers
Increased Risk of Toxicity
Debrisoquine Postural hypotension and physical collapse
Flecainide Ventricular tachyarrhythmias
Propafenone CNS toxicity and bronchoconstriction
Metoprolol Loss of cardioselectivity
Nortriptyline Hypotension and confusion
L-tryptophan Eosinophilia-myalgia syndrome
Indoramin Sedation
Thioridazine Excessive prolongation in QT interval
Failure to Respond
Codeine Poor analgesic efficacy
Tramadol Poor analgesic efficacy
Opioids Protection from oral opioid dependence
CYP2D6 Ultra-Rapid Metabolizers
Increased Risk of Toxicity
Encainide Proarrhythmic effects
Codeine Morphine toxicity
Failure to Respond
Nortriptyline Poor efficacy at normal dosages
Propafenone Poor efficacy at normal dosages
DRUG HYPERSENSITIVITY – ADR TYPE B (TYPE IV)
Human Leukocyte Antigen (HLA) system
Human Leukocyte Antigen (HLA) system
- Cell surface proteins regulate the immune system
- Located on chr 6 (major histocompatibility complex MHC)
Two types – Class I and II
HLA-A and HLA-B genes encode a cell surface protein that
bind peptides generated by proteolysis and extruded from
proteasomes. The presentation of these cell surface peptides
enables the immune system to distinguish self-proteins from
foreign proteins
DRUG HYPERSENSITIVITY – ADR TYPE B (TYPE IV)
Evidence many ADR involve inappropriate immune
response to a drug
Highly polymorphic (permits the fine-tuning of the
adaptive response) (ie., >7000 HLA alleles)
Formation of a covalent link between xenobiotic
and cellular protein, with HLA gene products
contribute to presenting peptide to T-cells
Direct interaction of drug with the HLA molecule,
leading to inappropriate T-cell response
DRUG HYPERSENSITIVITY – ADR TYPE B (TYPE IV)
Human Leukocyte Antigen (HLA)
Drug induced skin reactions
Stevens-Johnson syndrome
and toxic epidermal necrolysis
Monogenic vs. Polygenic
I.) Single-gene effects:
-SNPs in a single gene associated with altered drug metabolism or drug effects
-Many examples; drug metabolizing enzymes (CYP isozymes); physiological role
II.) Multi-gene effects (could be more important):
- Most drug effects determined by interplay of several gene products
- This because multiple genes involved in PK/PD of drugs
