The Personalized The Personalized Medicine Medicine Mr.G.Thirupugal Mr.G.Thirupugal M.Sc., Microbial Gene Technology M.Sc., Microbial Gene Technology Department of Microbial Technology Department of Microbial Technology School of Biological Sciences School of Biological Sciences Madurai Kamaraj University Madurai Kamaraj University By
The Personalized Medicine. By. Mr.G.Thirupugal M.Sc., Microbial Gene Technology Department of Microbial Technology School of Biological Sciences Madurai Kamaraj University. THERE IS AN OLD SAYING. The only difference between a medicine and a poison is the Dose - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
The Personalized The Personalized MedicineMedicine
Allele-specific nucleotide incorporation a.k.a. primer Allele-specific nucleotide incorporation a.k.a. primer
extension and single-base extension (SBE)extension and single-base extension (SBE)
Allele-specific DNA cleavageAllele-specific DNA cleavage
Assay Environment
Solid supports (such as oligonucleotide chips)Solid supports (such as oligonucleotide chips)
Homogenous solution Homogenous solution
Combination of the two environmentsCombination of the two environments
DNA CHIP
Other Methods of Detecting PolymorphismsOther Methods of Detecting Polymorphisms
SNP plentiful but not very informativeSNP plentiful but not very informative
Other optionsOther options
Haplotyping Haplotyping
Expression ProfilingExpression Profiling
HaplotypeHaplotype
SNPs that travel in groups, operate together to cause a certain drug SNPs that travel in groups, operate together to cause a certain drug response, usually within one generesponse, usually within one gene
Exist because certain polymorphisms tend to be linkedExist because certain polymorphisms tend to be linked
Discovered by sequencing DNADiscovered by sequencing DNA
Reduced complexity of genetic analysisReduced complexity of genetic analysis
Only a few common haplotypes in populationOnly a few common haplotypes in population
Each person has only two haplotypes (Each person has only two haplotypes (since each person has only since each person has only two copies of any particular gene)two copies of any particular gene)
Predict activity of gene more preciselyPredict activity of gene more precisely
Exons
Promoters
SNPs
Chromosomelocus of gene
Gene SNPs01
01
01
01
01
Haplotypes0 1 0 0 1
1 0 1 1 0
Causative Site
Haplotypes are a code for defining and tracking the isoforms of a gene
Gene Haplotypes
Genetically Based Optimization of Drug Dosing
Non-responders
Responders
Toxic responders
Genetically Based Optimization of Drug Dosing
Non-responders
Toxic responders
Absorption
Distribution
Metabolism
Elimination
Pharmacokinetic
Bioavailability
Drug Metabolisms
Variations In Drug Response
Environmental factors
Drug factors
Genetic factors
Drug Response
Absorption
Distribution
Target Interaction
Biotransformation
Excretion
Typical drug metabolism
Entrance into the body
Distribution
Drug cell interactions
Drug metabolism
Excretion
Oral Intravenous
Ingestion
Absorption
Distribution
Drug-cell interaction
Drug Metabolism
Excretion
[Drug Metabolism]
[Drug Metabolism]
[Drug Metabolism]
Distribution
Drug-cell interaction
Drug Metabolism
Excretion
Typical drug metabolism
Bioavailability of Drugs
Uptake of orally administered drug proceeds after the stomach passage via the small intestine.
In the liver, a series of metabolic transformation occurs
Drug Modification/Metabolism
Conjugation
Glucuronic acid
Glycine
Sulfates
Acetylation
Methylation
Mercapturic acid synthesis (not common)
Can produce inactive metabolites, more toxic compound or active
metabolites
Conjugation
Phenols, alcohols, carboxylic acids, compounds with amino or sulfhydryl groups generally form glucuronides
Aromatic acids form glycine conjugates
Phenols, alcohols or aromatic amines can undergo sulfate conjugation with donor being 3’-phospho-adenosine-5-phosphosulfate (PAPS)
That mean: The same genotype enables different phenotypes
The genotype, however, is determined by the individual DNA sequence. Human: two sets of chromosomes
The phenotype can be distinguished by the actual activity or the amount of the expressed CYP enzyme.
Depending on the metabolic activity, three major cathegories of metabolizers are separated: extensive metabolizer (normal), poor metabolizer, and ultra-rapid metabolizer (increased metabolism of xenobiotics)
CYP 2D6 Polymorphism
CYP 1A2 individual: fast, medium, and slow turnover of caffeine
CYP 2B6 missing in 3-4 % of the caucasian population
CYP 2C9 deficit in 1-3 % of the caucasian population
CYP 2C19 individuals with inactive enzyme (3-6 % of the caucasian
and 15-20 % of the asian population)
CYP 2D6 poor metabolizers in 5-8 % of the european,
10 % of the caucasian, and <1% of the japanese population. Over
expression (gene duplication) among parts of the african and oriental
population.
CYP 3A4 only few mutations
Polymorphisms Of Further CYPs
Affymetrix (US) has developped microarrays (gene chips) using immobilized synthetic copies of P450 nucleotides, that allow the identification of all clinically relevant allelic variants