Lecture 8- Pharmacogenetics part I

Question 1

pharmacogenetics and pharmacogenomics

Answer 1

• also called precision medicine
• using genetic and genomic info to more accurately predict drug responses

Question 2

goals for personalized medicine

Answer 2

1. identify genetic differences between people that affect drug response
2. develop genetic tests that predict an individual’s response
3. tailor medical treatments to the individual

• increase effectiveness
• minimize adverse side effects

Question 3

pharmacogenetics

Answer 3

• evaluates how an individual’s genetic makeup corresponds to their response to a particular medication

Question 4

pharmacogenomics

Answer 4

• combines pharmacogenetics with genomic studies
• uses large groups of patients to evaluate how candidate drugs interact with a range of genes and their protein products

Question 5

personalized medicine

Answer 5

• = population stratification
• looking at their genome
• actual base changes that vary throughout a population
• associated with drug being toxic and effective

Question 6

pharmacogenetics

Answer 6

• focused on known “major” drug metabolizing enzymes

Question 7

pharmacogenetics and drugs

Answer 7

ultra-drug metabolizer

• inactivation of the drug rapidly so it is ineffective

poor drug metabolizer

• end up with toxic doses of the drug

Question 8

pharmacogenetics and pro-drugs

Answer 8

ultra drug metabolizer

• pro-drug is metabolized to active form of drug to end up with toxic doses off the drug
• mutation in this gene required to activate the drug
• metabolizes too much of the drug, end up with too much active drug

poor drug metabolizer

• very little conversion of the pro-drug to the active form of the drug
• drug is ineffective

Question 9

main consequences of genetic polymorphisms

Answer 9

None

• outside of coding and regulatory regions
• synonymous substitution
• no impact on function of protein

Decrease or loss of function of the encoded protein

Increase in function of the encoded protein

Question 10

Decreased function

Answer 10

• less enzyme may be produced (decreased regulation)
• enzyme may not be complete (stop codon insertion)
• enzyme may not be as stable
• less binding affinity to substrate

Question 11

Increased in function

Answer 11

• more production (regulation or genomic copies)
• more stable
• more binding affinity

Question 12

Tuberculosis (TB)

Answer 12

• infectious disease caused by mycobacterium tuberculosis
• attacks the lungs, can affect other parts of the body
• airborne disease

Question 13

Isoniazid

Answer 13

• anti-biotic
• first used to treat tuberculosis
• metabolized in the liver via acetylation and then cleared from the body
• high incidence of peripheral neuropathy caused by the drug reaching toxic levels

Question 14

Looked at serum levels of isoniazid

Answer 14

• Look at serum levels of active drug
• Hoping for: bell curve with a normal distribution
• everyone gets to the same serum concentration at the same time
• Bimodal/trimodal graph
• some difference in the population that is driving why they don’t reach same conc
• Slower rate of acetylation: not cleared from the body
• mutations within NAT2 that result in slower acetylation

Question 15

NAT-1

Answer 15

• N-acetyltransferase gene
• little variation in the population

Question 16

NAT-2

Answer 16

• N-acetyltransferase gene
• several alleles which cause variation in the rate of acetylation of various drugs including isoniazid (and caffeine)
• Rapid acetylator –> considered wild-type
• Slow acetylator –> arious a.a substitutions in NAT2 leads to reduced efficiency of the gene

Question 17

thiopurines

Answer 17

class of drugs used to treat:

• acute lymphoblastic leukemia
• inflammatory bowel disease
• prevent organ rejection after transplantation
• other autoimmune diseases

Question 18

thiopuring methyltransferase (TPMT)

Answer 18

• enzyme that provides methylation of thiopurines
• thiopurines are converted into thioguanine nucleotides (TGNs)
• TGNs get inserted into DNA, inhibit DNA replication and can have toxic effects within the cell at high levels
• reduced TPMT activity can lead to fatal toxicity

Question 19

TPMT clinical relevance

Answer 19

• patients with two non0functional variant alleles are iven 6-10% of the standard dose of thiopurines
• heterozygous patients can be started on full dose but must be closely monitored to avoid toxicity

Question 20

normal alcohol metabolism

Answer 20

• Certain people don’t have a functioning ALDH2, get a build up of acetaldehyde à feeling not well

Question 21

ALDH2*2 mutation

Answer 21

• 50% east asian have ALDH2*2
• “alcohol flush”
• acetaldehyde is a known carcinogen also found in cigarette smoke
• increased risk for esophageal cancer

Question 22

disulfiram

Answer 22

• trade name Antabuse
• blocks ALDH2
• used for alcohol dependence

Question 23

conclusions

Answer 23

• patient responses to drugs: efficacy and toxicity
• personalized medicine
• cost of DNA sequencing has dramatically decreased
• DNA mutations can change drug metabolism

Question 24

examples of pharmacogenetics

Answer 24

• NAT-2: acetylation, isoniazid
• TMPT: methylation, thiopurines
• ALDH2: alcogol intolerance