2. What is polymorphism in genetics
The existence togather of many forms of DNA sequence at a
locus within the population.
A discontinuous genetics variation that results in different
forms or type of individual among the members of single
spacies
Polymorphism are generated by mutation in the gene for this
enzyme which cause decrease, increase or absent enzyme
expression or activity by multiple molecular mechanisms
3. Genetic polymorphisms of drug metabolizin enzyme give rise
to distinct subgroup In the population that differ in their
ability to perform certain drug biotransformation reaction.
4. Need of Metabolism
The metabolism of drugs and xenobiotic into more
hydrophilic metabolites is essential for their elimination from
body as well as for termination of their pharmacological
activity.
The enzyme system involved in biotransformation of drugs
are located primarily in the liver
The organs with significant metabolic capacity include GIT,
kidney and lungs.
These biotransformation reaction are carried out by CYP450
and by variety of transferases
5. Phases of drug metabolism
1. Phaes I (Oxidation,
Reduction, Hydrolysis)
2. Phase II
( Acetylation, Glucuronidation, Sulfation, Methylation)
All type of reaction covert relatively lipid soluble Drug into
relatively water soluble metabolites allowing for elimination.
6. Alleles
Genetic difference in drug metabolism are the result of
genetically based variation in alleles for gene that code for
gene that code for enzyme responsible for the metabolism of
drugs.
In polymorphism the gene contain abnormal Pair or
abnormal allele altered enzyme function.
Alleles: it is varient form of gene
7. Single nucleotide polymorphism
These are the position in genome where some individuals have
one nucleotide and other have different nucleotide.
It is variation at single position in a DNA sequence.
8. Cytochromes P450 (CYP450)
The polymorphic P450 (cyp) superfamily is most important
system involved in the biotransformation Of many Substances
include drug, toxins and carcinogens.
For drug metabolism the most important polymorphism are
those of the gene coding for CYP2C9, CYP2C19,CYP2D6 and
CYP3A4,CYP3A5, which can result in therapeutic failure or
severe adverse reaction
9. CYP2C19 AND Diazepam:
Plasma Diazepam half life is longer in individuals who are
homogeneous for difference CYP2C19*2 allele compared to other.
CYP2C9:
It is Major subfamily member in the liver.
Primarily responsible for Oxidative metabolism of important
compound warfarin, phenytoin, tolbutamide, glipezide.
CYP2C9*2 and 3 alleles associated with significant reduction in the
the metabolism.
10. CYP2C9 and warfarin:
CYP2C9*2 and 3 varient have higher risk of bleeding.
DPD:
Dihydropyrimidine dehydrogenase metabolise flurouracil and
endogenous pyrimidine
CYP3A4:
CYP3A4*1B is show that this varient May associated with slower
clearance of cyclosporine.
N acetyl transferase
Individuals are show the rapid or slower Acetylation.
Alleles contain G191A,T34C,A434C,G590A, and G857A.