Pharmaco- and Nutrigenomics

Question 1

What are pharmacodynamics vs. pharmacokinetics?

Answer 1

-dynamics - “what the drug does to the body”, the therapeutic effect it has over time

-kinetics - “what the body does to the drug”, relates to absorption, distribution, metabolism + elimination of the drug; change in conc. of drug within body over time

Question 2

Define pharmacogenomics.

Answer 2

study of how genetic variations in pharmacokinetic/-dynamic processes influence the effects and side-effects of a drugs

Question 3

What are “idiosyncratic responses” in relation to pharmacogenomics?

example?

Answer 3

genetic variations in genes not involved in the drug target or pharmacokinetic pathways, but still causing side effects related to the drug

ex: Favism - G6PD defic., can cause hemolysis in presence of anti-malarials (sulfanilamides)

Question 4

What is phenocopy and an example of it?

Answer 4

when environmental factors cause similar effects as genetic variants

ex: grapefruit inhibiting CYP3A4 > same effect as genetic defic.

Question 5

How do phase II and III clinical drug trials differ with respect to pharmacogenomics?

(specifics not totally important, but basic concepts prob are)

Answer 5

• Phase II trials - many human patients are treated with the drug vs. placebo
  
  • can then identify genetic markers (SNPs, etc.) for efficacy vs. inefficacy of the drug based on results
• Phase III trials - only patients with markers for efficacy are studied, and rarer/more severe side effects can be identified, as well as genetic markers for those

Question 6

What is suxamethonium chloride?

Its pharmacogenomic importance?

(next few cards on specif. drugs may not be super important, but were in lecture)

Answer 6

an nAChR agonist muscle relaxer

broken down by butyrylcholinesterase

some people don’t have it, others have low activity –> apnea + paralysis

Question 7

what is mercaptopurine?

its pharmacogenomic significance?

Answer 7

an immunosuppresive leukemia drug

broken down by thiopurine methyltransferase (TPMT)

3 genetic variants cause defic. –> dangerous myelosuppresion

“TMPT tests” can help doctors fine-tune dosage

Question 8

Variants in the genes for which enzymes cause 80% of all adverse drug responses?

What do these enzymes do and where are they found?

What are the 5 enzymes in this family that metabolize ~90% of drugs? (not super important… maybe the #1 plus 3 mentioned in a later card important in adverse events)

Answer 8

CYP-450 Enzymes (57 members)

in liver, oxidize endo-/xenobiotics

• CYP3A4 (35%)
• CYP2D6 (20%)
• CYP2C8/9 (16%)
• CYP1A/2 (11%)
• CYP2C19 (8%)

Question 9

What is the most common CYP450 enzyme listed in the FDA’s list of enzymes pharmacogenomically related to adverse drug events?

(How does it vary in different people?)

(bonus… 2nd most common in the list? how can they be tested for?)

Answer 9

CYP2D6

10% have slow-acting form; 7% have super-fast form; 35% are carriers of a non-functional allele

(CYP2C19 is 2nd; Amplichip CYP450 microarray test)

Question 10

Which CYP enzyme is important in metab. of a common anti-coagulant?

Describe the importance of its variants in treatment.

What other enzyme explains other variations in dosage of this drug?

Answer 10

CYP2C9

• 10% ppl have at least 1 slow-acting allele > can be treated with 50% doses of warfarin
• VKORC1 variants explain 30% of warfarin dose variation (mostly via a “low dose” haplotype)

Question 11

What two genes affect statin pharmacokinetics?

One for metabolism, another for elimination

Answer 11

CYP3A5 - also expressed in enterocytes; forms both active + inactive metabolites from statins > 10% euros have high expression > statins less effective

ABCB1 / MDR-1 - in hepatocytes; pumps statins into bile for elimination; certain SNP will incr. elimination

Question 12

Which gene influences the incidence of an adverse effect of statins?

Answer 12

SLC01B1

• a membrane transporter for hepatic uptake of statins; certain SNP (SLC01B1*5) can increase incidence of statin-induced myopathy

Question 13

What gene with a common (50%) variant affects pharmacogenomics of asthma treatment?

Answer 13

Beta2-R gene for albuterol/salbutamol

• short-acting B2R agonsists > bronchodilate
• a Gly16Arg variant decreases efficacy

Question 14

What less common variant affects another gene in asthma treatment?

Answer 14

ALOX5 - arachidonate 5-lipoxygenase

makes LTA4 from AA

treated with zileuton, an ALOX5 inhibitor

6% astham patients have mutant ALOX5, not affected by meds

Question 15

What is the difference between nutrigenetics and nutrigenomics?

Answer 15

nutrigenetics - how genetics influence the effect of nutrition

nutrigenomics - how nutrition influences gene expression

Question 16

What enzyme deficiency with a protective effect against malaria can be problematic in case of ingestion of certain foods?

Answer 16

Favism - X-linked G6PD defic.

• consumption of broad beans, antimalarial meds or use of henna can lead to hemolysis

Question 17

Which molecule in cholesterol metabolism can alter how a person responds to a cholesterol lowering diet?

Answer 17

Apo-E - on chylomicrons, VLDL, IDL and HDL

mediates cholesterol transport via APOE-Rs

• 3 main isoforms:
  
  • Apo-E2 (Cys-Cys, poor diet response, 8%)
  • Apo-E3 (Cys-Arg, normal, 77%)
  • Apo-E4 (Arg-Arg, good diet response, 15%)

Question 18

Which cholesterol metabolism gene can affect diet-related behavior?

(And is the most well-replicated nutrigenetic correlation studied)

Answer 18

APOA2 gene - found on HDL

265 T/C variation … CC patients tendency toward higher energy intake with high total fat/protein + obesity

Question 19

ALOX5, mentioned before in relation to asthma treatment, also plays a role in atherosclerotic risk.

How?

Answer 19

an ALOX5 VNTR variant can have negative effects on carotid intima-media thickness in case of consumption of higher dietary arachidonic or linoleic acid

BUT

the variant responds positively to increasing omega-3 intake

Question 20

What gene/mutation allows eskimos to eat their traditional high fat diet, but makes them more susceptible to “Western” diseases when their carb intake increases?

Answer 20

CPT1A gene (with Pro479Leu)

carnitine palmitoyltransferase 1 - regulator of LCFA oxidation

is protective against overproduction of ketones, but on western diet may cause hypoketotic hypoglycemia and thus high infant mortality

Question 21

What enzyme in purine metabolism has a mutation which can influence CV disease and developmental abnormalities?

Answer 21

MTHFR - methylene H4F reductase

with the ALA222VAL variant + too little folate intake, homocysteine will increase leading to atherosclerosis and spina bifida

Question 22

What enzyme in alcohol metabolism has variants which affect alcohol’s protective effect on cardiovascular risk?

Answer 22

alcohol dehydrogenase 3 (ADH3)

• γ1 type is a fast metabolizer; γ2 is slow
• people with γ2γ2 genotype have lowest CV risk / highest HDL when drinking a couple drinks/day

Question 23

Variants of what gene can have a positive effect on Parkinson’s disease in heavy coffee drinkers?

Answer 23

GRIN2A - an NMDA-Glu-R subunit that regulates excitatory neurotransmission in the brain