Lecture 10 Flashcards
Pharmacogenetics vs pharmacogenomics
However, pharmacogenetics generally refers to monogenetic variants that affect drug response, whereas pharmacogenomics refers to the entire spectrum of genes that interact to determine drug efficacy and safety.
Goals of Pharmacogenetics
- Optimize drug therapy
2.Limit drug toxicity based on an individual’s genetic profile.
Overall aim of pharmacogenetics
pharmacogenetics aims to use genetic information to choose a drug, drug dose, and treatment duration that will have the greatest likelihood for achieving therapeutic outcomes with the least potential for harm in each patient.
Pharmacogenetics concept
To use genetic information specific to an individual patient to preselect a drug that will be effective and not cause toxicity.
= Personalized medicine
Personalised medicine
Relies on identifying.. that allows…
The approach relies on identifying genetic, epigenomic, and clinical information that allows the breakthroughs in our understanding of how a person’s unique genomic portfolio makes them vulnerable to certain diseases.
PM approach is a complete extension of traditional approach (One-Size-Fits-All) to increasing our ability to predict which medical treatments will be safe and effective for individual patient, and which ones will not be, based on the patient’s unique genetic profile.
What does a gene contain and their purpose?
1.exonsthat encode for the final protein,
- intronsthat consist of intervening noncoding regions, and regulatory sequences
3.regulatory regionsthat control gene transcription.
Genetic Variation:
Describe the following variations;
1.Single-nucleotide polymorphisms (SNPS)
2.Insertion/deletion polymorphisms
3. Tandem repeats
4.Frameshift mutation
5. Defective splicing
6.Aberrant splice site
7.Premature stop codon
SNPs are the most common genetic variations in human DNA.
Insertion-deletion polymorphisms,in which a nucleotide or nucleotide sequence is either added to or deleted from a DNA sequence.
Tandem repeats,in which a nucleotide sequence repeats in tandem
Frameshift mutation, in which there is an insertion/deletion polymorphism, and the number of nucleotides added or lost is not a multiple of 3, resulting in disruption of the gene’s reading frame.
Defective splicing,in which an internal polypeptide segment is abnormally removed, and the ends of the remaining polypeptide chain are joined.
Aberrant splice site,in which processing of the protein occurs at an alternate site.
Premature stop codon polymorphisms,in which there is premature termination of the polypeptide chain by a stop codon
CYP450 pathway:
Role of the liver?
biotransformation reactions are carried out by…
The enzyme systems involved in the biotransformation of drugs are localized primarily in the liver.
These biotransformation reactions are carried out by CYPs (cytochrome CYP450 isoforms) and by a variety of transferases.
Pathways of drug metabolism are classified as either:
Phase I reactions: oxidation, reduction, hydrolysis
Phase II reactions: acetylation, glucuronidation, sulfation, methylation
Effect of Polymorphism in Genes for Drug metabolizing Enzyme
How are polymorphisms generated?
Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions.
Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms.
SNP’s and drug metabolizers:
What is a SNP and effect?
what determines the activity and effectiveness of the enzyme?
Overall function of then enzyme is the …
Single changes in one allele of a gene responsible for a variety of metabolic processes including enzymatic metabolism.
The combination of alleles encoding the gene determines the activity and effectiveness of the enzyme.
The overall function of the enzyme is the phenotype of enzyme function.
SNP and drug metabolizers: How many wild type alleles/defective alleles?
Poor metabolisers
Intermediate metabolisers
Normal metabolisers
1.Poor metabolizers
- Two defective alleles (eg: CYP2D64/5 and CYP2D64/4)
Combination of alleles including one resulting in no enzyme (ex: CYP2D65 and CYP2D64 deletion)
2.Intermediate metabolizers
Heterozygous – having only one wild type allele and one defective allele
3.Normal metabolizers
Carry wild type alleles (ex: CYP2D61/3).
Wild type alleles encode genes for normal enzyme function
4.Extensive metabolizers
Carry one wild type and one amplified gene
ex: CYP2D61/2, CYP2D6A/1a, and CYP2D61A/5
5.Ultra-rapid metabolizers
Carry two or more copies of amplified gene
ex: CYP2D62/3
SNP and drug metabolizers: Genetic changes influence on substrate?
Genetic changes may inactivate or reduce enzyme activity leading to increase in the substrate drug.
Genetic duplication may increase enzyme activity resulting in lower levels of substrate drug.
Polymorphism – Drug interaction
How do Polymorphism affect enzyme?
Inhibitor and inducer
Polymorphisms affect drug interactions by altering the effect of inhibitors and inducers on the enzyme.
Results in an exaggerated effect or minimal effect on the substrate
Inhibitor: An enzyme inhibitor is a molecule, which binds to enzymes and decreases their activity.
Inducer: drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme.
Extensive Metabolizers (EM) - Inhibitors affect on substrate level
In a ____ metabolizer, the level of substrate drug remains ___ because the metabolism of the substrate is much ____ than normal.
Extensive metabolizer: level of substrate drug is normally low due to rapid metabolism by the enzyme.
An inhibitor to the enzyme will inhibit the extensive metabolism and cause significant elevations in the substrate drug.
