SUBHASREE PAL BIOTECHNOLOGY 3rd year , 6th sem Roll-101020546 BT-694

What is pharmacogenomics? Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs.

The term ‘Pharmacogenomics’ comes from the words ‘pharmacology’ (the science of drugs) and ‘genomics’ (the study of genes and their functions) and is thus the intersection of pharmaceuticals and genetics.

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Enzymes involved in Pharmacogenomics:

Cytochrome P450 (CYP) family of enzymes is involved in metabolism of several drugs.

Example: CYP2D6 enzyme

CYP3A4 enzyme

CYP2A6enzyme CYP2B6 enzyme CYP2C9enzyme CYP2C19enzyme CYP2E1 enzyme

Effect of Cytochrome P450 Enzymes on Drug Metabolism:

Cytochrome P450 enzymes are essential for the metabolism of many medications.

The most significant enzymes are : CYP3A4 and CYP2D6.

These enzymes are Haemoglobin containing mono-oxygenase and are divided into 2 primary groups :

Steroidogenic and Xenobiotic

Steroidogenic and Xenobiotic P450 Enzymes:

Steroidogenic P450 enzymes :

These enzymes are found in prokaryotes and in eukaryotes.

Xenobiotic P450 enzymes :

These enzymes are found in smooth endoplasmic reticulum of eukaryotes.

Xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. 

ADME property of drug on drug metabolism:

ADME: Absorption Distribution Metabolism Excretion.

ADME describes the deposition of pharmaceutical compounds within an organism.

The 4 criteria(ADME) all influence the drug levels and kinetics of drug exposure to the tissue and hence influence the performance and pharmacological activity of the compound as a drug.

Absorption : Drug Absorption is the movement of drug from its site of

administration into the blood stream.

Absorption critically determines the compound's bioavailability.

Sites of Drug Absorption : For a compound to reach a tissue, it usually must be taken into the bloodstream, often via mucous surfaces like the digestive tract (intestinal absorption), before being taken up by the target cells.

Distribution : The drug needs to be carried to its effector site via blood stream,

from there the compound is distributed into muscles and organs.

Different Drug Distribution Patterns :

Pattern1 : The drug remains largely within the vascular system such as heart, arteries.

Example :- Dextran. Pattern2 : Low molecular water soluble compounds such as ethanol

and few sulphonamides becomes uniformly distributed throughout the body water.

Example :- Disprine. Pattern3 : A few drugs are concentrated specifically in one or more

tissues that may or may not be the site of action. Example :- Iodine-Iodine is concentrated by the thyroid gland. Pattern4 : Most drug exhibit a non-uniform distribution in the body.

It is the combination of Pattern1, Pattern2 and Pattern3.

Metabolism : Cytochrome P450 enzymes are essential for the metabolism of

many medications. The most significant enzymes are : CYP3A4 and CYP2D6.

Sites of Drug Metabolism :

At Organ level : The liver is the primary organ of drug metabolism. The lungs, kidney, intestine, skin and placenta can also carry out drug metabolism.

At Cellular level : Most enzymes involved in drug metabolism are located within the lipophilic membrane of smooth endoplasmic reticulum.

At Biochemical level :

1. Phase1 reaction : This refers to those which convert a drug to a more polar compounds by introducing or unmasking polar functional group such as OH, NH2 or SH. Some Phase1 product are not eliminated properly and hence undergo to the Phase2 reaction.

2. Phase2 reaction : This reaction involves conjugation of newly established polar group with endogenous compounds such as H2SO4, Acetic Acid or Amino Acid(typically Glycine). Eg: Glucuronide formation is the most common Phase2 reaction.

Elimination : The kidney is the most important organ for the excretion of drugs

and their metabolites.

Some compounds are also excreted via bile, sweat and saliva.

Mechanism of Drug Elimination :

Renal Glomerular Filtration : It permits the passage of most drug molecules but restricts protein bound drugs. Example : Digoxin

Renal Tubular Secretion : The kidney can actively transport some drugs against a concentration gradient, even if the drugs are protein bound.

Renal Tubular Reabsorption :

Many drugs are passively reabsorbed in the distal renal tubules.

Reabsorption is influenced by physiochemical factors.

Biliary Excretion :

Many drugs and their metabolites are passed into the small intestine via bile and may undergo enterohepatic cycle.

Single-nucleotide polymorphisms(SNPs) effect on Pharmacogenomics :

Single Nucleotide Polymorphism (SNP):

GAATTTAAG

GAATTCAAG

SNPs are defined as Single base-pair positions in genomic DNA that vary among individuals in one or several populations.

SNPs are believed to underlie susceptibility to such common diseases as cancer, diabetes, and heart disease and to contribute to the traits that make individuals unique.

SNPs are used as genomic biomarkers.

Hence SNP analysis can be used to enhance drug discovery and development.

DNA molecule 1 differs from DNA molecule 2 at a single base-pair location (a C/T polymorphism)

Personalized medicine :

Herceptin (breast cancer, target: Her2 gene)

Erbitux (colorectal cancer, target: EGFR)

Tarceva (lung cancer, target: EGFR)

Strattera (attention-deficit/hyperactivity disorder,

Metabolism: P4502D6)

6-mercaptopurine(6-MP) (leukemia, Metabolism: TPMT)

Antivirals (i.e. resistance based on form of HIV)

etc. and the list is growing rapidly ...

Pharmacogenomics:-A Case Study :

Applications of Pharmacogenomics :

Oncology :

Pharmacogenomics can be used to isolate and identify specific chemotherapeutic agents that have limited toxic side effects to an individual, but still attack and destroy the cancerous tumour.

Pharmacogenomics can be applied to individuals having dihydropyrimidine dehydrogenase(DPD) deficiency.

Cardiovascular disorders :

In cardiovascular disorders the main concern is response to drugs such as warfarin, clopidogrel, beta-blockers and statins.

CYP2C9 enzyme is involved in warfarin metabolism.

The CYP2D6 enzyme is used to treat hypertension and drugs often prescribed to control heart problems.

Neurology :

Pharmacogenomics can be used in the treatment of Alzheimer’s disease.

Alzheimer’s disease has two forms – familial and sporadic.

Apolipoprotein E isoform 4 (ApoE-4) is a gene which is associated with Alzheimer’s disease.

Asthma :

Pharmacogenomics can be used in the treatment of Asthma.

Genotyping for individual pharmacogenomics responses may be useful in establishing an anti-asthmatic therapy.

Bibliography :

Bioinformatics Methods and Applications (Genomics, Proteomics and Drug Discovery) Book.

www.google.com

From Wikipedia, the free encuclopedia.

Thank You……