Download 6 N-Acetyltransferase Activity

Session
8
Medical Genetics
Pharmacogenetics
J a v a d
F a s a
J a m s h i d i
U n i v e r s i t y
o f
M e d i c a l
S c i e n c e s ,
N o v e m b e r
2 0 1 6
What is Pharmacogenetics?
The sensitivity to drugs is different among people
Individual differences in response to drugs in humans are,
often genetically determined
Study of genetically determined variations that are
revealed solely by the effects of drugs
Pharmacogenetics is now used to describe the influence of
genes on the efficacy and side effects of drugs
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Stages of Metabolism of a Drug
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Various types of response to different drugs
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Image from: Thompson & Thompson Genetics in Medicine, 8e
N-Acetyltransferase Activity
The metabolism of isoniazid shows two: rapid and slow
inactivators.
To avoid side effects and also efficient treatment dose should
be controlled
Slow inactivators are homozygous for an AR allele of the liver
enzyme N-acetyltransferase, with lower activity levels
Metabolize several other drugs include hydralazine which is an
antihypertensive, and sulfasalazine ,used to treat Crohn
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N-Acetyltransferase Activity
N-acetyltransferase activity varies in different populations.
There are three genes for N -acetyltransferase in Humans:
NATP: pseudogene , is not expressed
NAT1: No differences in activity between individuals
NAT2: Responsible for the inherited polymorphic variation
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Glucose 6-Phosphate Dehydrogenase Variants
Some people are sensitive to primaquine
Defective X-linked, glucose 6-phosphate dehydrogenase
(G6PD).
Sensitive to many other compounds, including phenacetin, and
certain sulfonamides
The first recognized Pharmacogenetic disorder, having been
described by Pythagoras around 500 Be.
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Contribution of individual cytochrome P-450 enzymes to drug metabolism
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Image from: Thompson & Thompson Genetics in Medicine, 8e
Coumarin Metabolism
Coumarin anticoagulant drugs, such as warfarin, are used to
prevent the blood from clotting
Warfarin is metabolized by the cytochrome P450 enzyme
encoded by the CYP2C9 gene
CYP2C9*2 and CYP2C9*3 result in decreased metabolism
Require a lower warfarin dose to maintain their target INR
range and may be at increased risk of bleeding
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Debrisoquine Metabolism
There is a bimodal distribution in the response to the drug in the
general population.
Approximately 5% to 10% of persons of European origin are poor
metabolizers
One of the P450 family of genes on chromosome 22, known as
CYP2D6.
This enzyme is involved in the metabolism of more than 20% of
prescribed drugs including:
β-blockers metoprolol and carvedilol
The antidepressants fluoxetine and imipramine
The painkiller codeine
The anti-cancer drug tamoxifen
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Pharmacogenetics & Pharmacogenomics
Personalized or individualized medicine, where the treatment is
dependent on the individual's genotype
Pharmacogenomics is the study of the interaction of an
individual's genetic makeup and response to a drug.
Inherited variation at the DNA level play an essential role in
determining the variability in responses to a drug
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Avoid Adverse Events
The objective is to identify a genetic profile that characterizes
patients who are more likely to suffer an adverse event.
The best example is abacavir, used to treat HIV. About 5% of
patients show fatal hypersensitivity to abacavir and this limited
its use
A strong association with the HLA allele B*5701 was proven in
2002. Today testing for B*5701 is routine practice before
abacavir is prescribed.
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Improve Efficacy
Drug should be prescribed only to those patients likely to
respond to them.
Herceptin is an antibody that targets overexpression of HER2/neu
protein observed in approximately one-third of patients with
breast cancer.
Patients are prescribed herceptin only if their tumor has been
shown to overexpress HER2/neu.
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