Pharmacogenomics

Question 1

G6PD deficiency: Heredity

Answer 1

X linked recessive

male predominance

most common in middle eastern decent

Question 2

Plasma Cholinesterase deficiency: Heredity

Answer 2

Autosomal recessive

highest prevalence in caucasian pop

Question 3

Acute Intermittent Porphyria: Heredity

Answer 3

Autosomal dominant

female predominance (hormonal enzyme induction)

Question 4

Causes of acute intermittent porphyria exacerbation

Answer 4

spontaneous or result from exposure to drugs, hormones or other compounds
drugs that induce CYP system often also induce ALA synthase and can cause exacerbation (barbs, estrogens, many anesthetic/sedative drugs)
severely restricted caloric intake

Question 5

Acute Intermittent Porphyria: manifestation

Answer 5

tissue site: liver

pain in abdomen and back
nausea
tachycardia without fever
seizure
normal to dark amber urine

Question 6

NAT2 (N-acetyltransferase) deficiency: heredity

Answer 6

Single recessive gene (27 reported NAT2 alleles)

2 common alleles (NAT25, NAT26) account for 90+% of slow acetylators

NAT2 has no introns (just protein - coding regions)

40-70% Caucasian and African American
10-20% Japanese and Canadian Eskimo
80+% Egyptians

Question 7

G6PD deficiency

Answer 7

hemolysis, RBC breakdown –> hemolytic anemia

Question 8

What is glucose 6 phosphate dehydrogenase?

Answer 8

• part of pentose phosphate pathway

- provides reducing energy (NADPH) to cells to protect them from ROS

Question 9

G6PD deficiency usually goes unnoticed until…

Answer 9

oxidative stress!!

fava beans, legumes ,sulfonamides, antimalarials?

Question 10

NAT2 deficiency: what is it?

Answer 10

Deficiency in N - acetyltransferase (NAT2) –> part of phase 2 metabolism

1st observed with isoniazid.

Question 11

Isoniazid: slow acetylators and fast acetylators)

Answer 11

slow acetylators: more prone to suffer from isoniazid toxicity (peripheral neuropathy)

fast acetylators: more prone to suffer from hepatotoxicity

Question 12

Acetyltransferase also important in metabolism of which other drugs besides isonizaid?

Answer 12

hydralazine, procainamide, dapsone, and sulfonamides;

deficiency can result in a lupus type syndrome (autoimmune disease skin, joints, kidneys, etc)
not lupus, but similarities

Question 13

Phase I: Functionalization reaction

Answer 13

~80% of drug metabolized this way

• exposes a functional group
• small increase in polarity
• EX. oxidation, reduction, hydrolysis

Question 14

Phase II: Conjugation reaction

Answer 14

• large polar compound attached to functional group (covalent bond)
• large increase in polarity
• EX: acetylation, glucuronidation

Question 15

Goals of Human Genome Project

Answer 15

• identify all the genes
• determine sequences of base pairs that make up human DNA
• store this information
• improve data analysis tools
• transfer related technologies to private sector
• address ethical, legal, and social issues (ELSI) that may arise from the project

Question 16

R warfarin metabolized by what enzyme?

Answer 16

CYP3A4, 1A2, 1A1

Question 17

S warfarin metabolized by what enzyme?

Answer 17

CYP2C9

S warfarin is 5X more potent than R warfarin

Question 18

CYP2C9 SNP: wild type variant *1

Answer 18

metabolizes warfarin normally

Question 19

CYP2C9 SNP: polymorphic variant *2

Answer 19

reduced warfarin metabolism by 30%

Question 20

CYP2C9 SNP: polymorphic variant *3

Answer 20

reduced warfarin metabolism 90%

Question 21

What is VKORC1 and its purpose?

Answer 21

target enzyme for warfarin

warfarin inhibits VKORC1 and prevents the active form of vitamin K

Question 22

G1639A polymorphism and associated warfarin dosing

Answer 22

have lower levels of the VKOR enzyme – would need less warfarin

Question 23

Clopidogrel: Class and MOA

Answer 23

antiplatelet - prodrug

MOA: binds to ADP receptors on platelets, prevents aggregation and thrombosis

-active metabolite binds to the P2RY12 receptor, irreversibly blocks ADP binding and receptor activation, thus inhibits blood clotting

Question 24

Enzyme responsible for clopidegrel metabolism

Answer 24

metabolized by CYP2C19 to active form

Question 25

CYP2C19 genetic variant *2, 3, 4 and 5 and associated consequences

Answer 25

CYP2C19 Activity: none Since no metabolism, does not metabolism to active form so no effect of drug. At risk for clotting issue: MI, stroke, etc. *most genetic testing focused on genetic variant 2 because risk is more catastrophic and effects largest group of population*

Question 26

CYP2C19 genetic variant *17 and associated consequence

Answer 26

CYP2C19 activity: increased at risk for bleeding

Question 27

Enzyme responsible for codeine metabolism.

Answer 27

CYP2D6: metabolizes codeine to active form, ~10% converted to morphine, partially by CYP2D6

Question 28

CYP2D6 activity: none. What type of metabolizer are they and what is the associated effect?

Answer 28

poor metabolizer almost no effect of drug, do not feel pain relief

Question 29

CYP2D6 activity: high. What type of metabolizer are they and what is the associated effect?

Answer 29

ultrarapid metabolizer metabolize codeine too efficiently potential for respiratory depression and overdose

Question 30

Tamoxifen: Class, use, metabolism by which enzyme.

Answer 30

Estrogen receptor (ER) antagonist - PRODRUG Used to treat ER+ breast CA PRODRUG metabolized by CYP2D6 --CYP2D6 is the rate limiting enzyme in the catalysis of tamoxifen to metabolites with greater affinity for the ER

Question 31

What is GINA?

Answer 31

Genetic information nondiscrimination act (2008) protects Americans from discrimination based on genetic information in health insurance and employment