This document discusses pharmacogenomics and its applications. Pharmacogenomics is the study of how genetics affect individual responses to drugs. It can be used to maximize drug efficacy, minimize toxicity, and personalize medicine by predicting patient responses and aiding new drug development. The document also discusses genetic mapping, cloning, genetic variation, drug metabolism pathways, and polymorphisms in genes encoding drug-metabolizing enzymes and transporters.

1. Sham Higginbottom University Agriculture, Technology and
Sciences(SHUATS)
Prepared by:
SHIV CHANDRA
ID- 22MPHACLY001
M. Pharm Pharmacology
1st year

2.  Pharmacogenomics is the study of the role of
the genome in drug response.
 It deals with the influence of acquired and
inherited genetic variation on drug response in
patients by correlating gene expression or single-
nucleotide polymorphisms with pharmacokinetics
and pharmacodynamics.

3.  Maximize drug efficacy
 Minimize drug toxicity
 Predict patients who will respond to intervention
 Aid in new drug development
Research in the field of pharmacogenetics is moving
in two main directions:
1. Identify specific genes and their products that are
associated with different diseases and may be targets
for new treatments.
2. Identification of genes and allelic variants of genes
that may affect the response to drugs for disease.

4.  First recognized by Pythagoras around 510
BC(some people eat fava- anaemia)
 Fredrich Vogel – first named pharmacogenetics in
1959
 Sir Archibald Garrod – the role of genetics in
response to drug in 1990

6.  Genetic polymorphism
 Epigenetic and other factors
 Pharmacogenomics biomarker
 Personalised medicine

7.  To predict a patient’s response to drug
 To develop customized prescriptions
 To minimize or eliminate adverse effects
 To improve efficacy and patient compliance
rational drug development
 To improve the accuracy of determining
appropriate dosages of drugs
 To screen and monitor certain diseases
 To develop more powerful, safer vaccines
 To allow improvements in drug R&D and the
approval of new drugs

8. 1. Cancer
2. Neurodegenerative disease
3. Thrombosis
4. Cardiovascular disease
5. Anaesthesia
6. Type-2 diabetes
7. Depression

9.  The process of determining the location of gene on
chromosome.
 The gene mapping identify the locus of gene and
their relative distance within genome.

10. 1. Genetic mapping
2. Physical mapping
3. Comparative mapping

11. Genetic mapping:
 Linear description of DNA marker/gene on a given
chromosome with closely placed marker being
inherited together more often.
 Linkage mapping
 Pedigree
 Polymorphic marker.

12. Physical mapping:
 Physical location on the chromosomes, relating
more towards exact positioning of gene element.
 Cytogenetic
 Somatic cell
 Radiation hybrid
 Restriction mapping

13. Comparative mapping:
 Genome/genetic map, graphic representation of the
relative position of gene in a DNA sequences.
 Gene sequence
 Data base
 DNA chips

14.  Gene therapy
 Cancer
 Milk production
 Plant breeding genetic disease

15.  A clone is a genetically identical copy of an
organism and it may be naturally occuring or
created in lab.
 Through the process of asexual reproduction,
organism such as bacteria and some plant create
offspring that are genetically identical to the
parent.

16. 1. Genetic cloning
2. Reproductive cloning
3. Therapeutic cloning

17.  Making multiple copies of a single gene.
 The insertion of fragment of DNA carrying a gene
into a cloning vector and subsequent propagation
of recombinant DNA molecule into many copies is
known as gene cloning.

18. Basic steps of gene cloning:
 Construction of recombinant DNA molecule.
 Transport of the recombinant DNA to the host cell.
 Multiplication of recombinant DNA molecule.
 Division of the host cell.
 Numerous cell division resulting in the clone.

19.  Reproductive cloning involves crating and animal
that is genetically identical to a donor animal
through somatic cell nuclear transfer.
 In reproductive cloning the newly created embryo
is placed back into the uterine environment where
it can implant and develop.
 Example the sheep Dolly

20.  In therapeutic cloning an embryo is created in a
similar way to that of reproductive cloning but the
resulting cloned cells remain in a dish in the lab,
they are not implanted into a female uterus.

21.  Genetic variation is a measure of the variation that
exist in the genetic makeup of individual within
population.
 Gene variation is important to the process of
natural selection.

22. Causes of genetic variation:
 Environmental factor
 Genetic factor
Factor affecting genetic variation:
 Mating partners are important
 Random forces lead to genetic drift
 Distribution
 migration

23.  Gene replacement and gene addition
 DNA and RNA targeting and delivery methods
 Gene therapy
 Genetic testing
 Gene repair therapies
 Viral vector or vehicles used to transfer DNA and
RNA

24.  Genetic polymorphisms of drug metabolising
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.

25. Drug metabolism:
 The metabolism of drugs and other xenobiotics
into more hydrophilic metabolites is essential for
their elimination from the body, as well as for
termination of their biological and
pharmacological activity.
 Drug metabolism or biotransformation reactions
are classified as either phase 1 functionalization
reactions or phase 2 biosynthetic (conjugation
reactions).

26. Pathways of drug metabolism are classified as
either:
 Phase 1 reaction: oxidation, reduction, hydrolysis
 Phase 2 reactions: acetylation, glucuronidation,
sulfation, methylation
 Both types of reaction convert lipid soluble to
inactive and more water soluble metabolites,
allowing for more efficient systemic elimination.

27.  Genetic differences in drug metabolism are the
result of genetically based variation in allele for
gene that code for enzymes responsible for the
metabolism of drugs.
 In polymorphisms, the genes contain abnormal
pairs or multiples or abnormal alleles leading to
altered enzyme function.
 Differences in enzyme activity occur at different
rates according to racial group.

28.  Single changes in one allele of gene is 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.
Phenotype: the observable physical or biochemical
characteristics determined by both genetic makeup
and environmental influences.

29. Types of metabolizers
Poor metabolizers:
 Two defective alleles eg- CYP2D6 4/5 and CYP2D6 4/4
 Combination of alleles including one resulting in no enzyme
eg- CYP2D6*5 and CYP2D6*4 deletion
Intermediate metabolizers:
 Heterozygous- having only one wild type allele & defective
allele
Normal metabolizers:
 Carry wild type alleles eg- CYP2D6*1/3
 Wild type alleles encode genes for normal enzyme function.

30. Extensive metabolizers:
 Carry one wild type and one amplified gene eg-
CYP2D6*2, CYP2D6*1a and CYP2D6*1A/*5
Ultra-rapid metabolizers:
 Carry two or more copies of amplified gene eg-
CYP2D6*2/*3

31.  The polymorphic P-450 enzyme super family is
the most important system in the biotransformation
of many endogenous and exogenous substances.
 Genotype for CYP polymorphs provides important
genetic information that helps to understand the
effects of xenobiotics on human body.
 For drug metabolism the most important
polymorphisms are those of the genes coding for
CYP2C9,CYP2C19, CYP2D6 and CYP3A4/5
which can result in therapeutic failure or severe
adverse reactons.

32.  Transporters are those proteins that carry either
endogenous compounds or xenobiotics across
biological membranes.
 The extent of expression of genes coding for transport
proteins can have profound effect on the bioavailability
and pharmacokinetics of various drugs.
 Transporters that serves as efflux pumps on a cell
membrane can remove drugs from the cell before they
can act.
 There are two types of transporter-
1. ATP binding cassette(ABC)
2. Solute carrier(SLC)

33.  7-trans membrane helices connected by alternating
cytosolic and extra cellular loop
 C terminal: inside the cell
 N terminal: extra cellular region
 Extracellular portion has unique messenger
binding site
 Cytosolic loop allow receptor to interact with G
protein.

34. Genetic variations may be due to-
 Sequence variations of the human genome
 Structure and function of GPCRs
 GPCR coupling to G proteins and other signaling
pathways
 GPCR binding pockets
 Spontaneous GPCR signaling
 Multiple receptor conformations with distinct
functions.

35.  Proteomics is the study of composition, structure, function
and interaction of the proteins directing the activity of each
living cell.
Types of proteomics-
1. Interaction proteomics: protein protein interaction used
to identify binary proteins interaction, protein complexes
and interactome.
2. Expression genomics: protein quantification. The level
of any protein in the cell at any given time is controlled
by-
 Rate of transcription of the gene.
 Rate of degradation of protein
 Efficiency of translation of mRNA into the protein

36. Application
 Manufacturing and production of potential new drug
for treatment of diseases eg- diabetes, cancer.
 This depend upon genome an information in the form
of protein expression
 Manufactured drug to the inactive protein involved in
disease
 Computer software used as target for new drug
discovery
 Competitive molecule that inactivates the enzyme
 Forms basic new drug discovery tool.

37.  Focusing on the structure, function,
evolution, mapping and editing of genome.
 A genome is an organism’s complete set of
DNA; including all of its genes.

38.  Molecular medicine
 Genes for disease succeptibility
 Microbial genomics
 Risk assessment
 Bioarchaelogy, anthropology, evolution
 DNA identification, forensic
 Agriculture, breeding bio processing
 Increased rate of genetic improvement
 Detect abnormalities
 Animal cloning
 Transgenic animals

39.  Large scale study of small molecule.
 Metabolites within the cells, biofluids, tissue or
organisms.
 Collectively this small molecules and their
interaction within a biological system are known
as metabolome.

40. Application:
 Pharmacology and pre-clinical drug trials
 Toxicology
 Transplant monitoring
 New born screening
 Clinical chemistry
 Tools for functional genome

41.  The study of the effects of foods and food
constituents on gene expression.
 It will identify the gene involved in physiological
responses to diet and the gene in which small
changes called polymorphism and the influence of
environmental factors on gene expression.
Application:
 Cancer treatment
 Obesity
 Aging