Pharmacogenomics Flashcards

1
Q

G6PD deficiency: Heredity

A

X linked recessive

male predominance

most common in middle eastern decent

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2
Q

Plasma Cholinesterase deficiency: Heredity

A

Autosomal recessive

highest prevalence in caucasian pop

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3
Q

Acute Intermittent Porphyria: Heredity

A

Autosomal dominant

female predominance (hormonal enzyme induction)

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4
Q

Causes of acute intermittent porphyria exacerbation

A

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

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5
Q

Acute Intermittent Porphyria: manifestation

A

tissue site: liver

pain in abdomen and back
nausea
tachycardia without fever
seizure
normal to dark amber urine
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6
Q

NAT2 (N-acetyltransferase) deficiency: heredity

A

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

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7
Q

G6PD deficiency

A

hemolysis, RBC breakdown –> hemolytic anemia

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8
Q

What is glucose 6 phosphate dehydrogenase?

A
  • part of pentose phosphate pathway

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

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9
Q

G6PD deficiency usually goes unnoticed until…

A

oxidative stress!!

fava beans, legumes ,sulfonamides, antimalarials?

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10
Q

NAT2 deficiency: what is it?

A

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

1st observed with isoniazid.

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11
Q

Isoniazid: slow acetylators and fast acetylators)

A

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

fast acetylators: more prone to suffer from hepatotoxicity

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12
Q

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

A

hydralazine, procainamide, dapsone, and sulfonamides;

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

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13
Q

Phase I: Functionalization reaction

A

~80% of drug metabolized this way

  • exposes a functional group
  • small increase in polarity
  • EX. oxidation, reduction, hydrolysis
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14
Q

Phase II: Conjugation reaction

A
  • large polar compound attached to functional group (covalent bond)
  • large increase in polarity
  • EX: acetylation, glucuronidation
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15
Q

Goals of Human Genome Project

A
  • 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
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16
Q

R warfarin metabolized by what enzyme?

A

CYP3A4, 1A2, 1A1

17
Q

S warfarin metabolized by what enzyme?

A

CYP2C9

S warfarin is 5X more potent than R warfarin

18
Q

CYP2C9 SNP: wild type variant *1

A

metabolizes warfarin normally

19
Q

CYP2C9 SNP: polymorphic variant *2

A

reduced warfarin metabolism by 30%

20
Q

CYP2C9 SNP: polymorphic variant *3

A

reduced warfarin metabolism 90%

21
Q

What is VKORC1 and its purpose?

A

target enzyme for warfarin

warfarin inhibits VKORC1 and prevents the active form of vitamin K

22
Q

G1639A polymorphism and associated warfarin dosing

A

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

23
Q

Clopidogrel: Class and MOA

A

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

24
Q

Enzyme responsible for clopidegrel metabolism

A

metabolized by CYP2C19 to active form

25
Q

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

A

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

26
Q

CYP2C19 genetic variant *17 and associated consequence

A

CYP2C19 activity: increased

at risk for bleeding

27
Q

Enzyme responsible for codeine metabolism.

A

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

28
Q

CYP2D6 activity: none.

What type of metabolizer are they and what is the associated effect?

A

poor metabolizer

almost no effect of drug, do not feel pain relief

29
Q

CYP2D6 activity: high.

What type of metabolizer are they and what is the associated effect?

A

ultrarapid metabolizer

metabolize codeine too efficiently

potential for respiratory depression and overdose

30
Q

Tamoxifen: Class, use, metabolism by which enzyme.

A

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

31
Q

What is GINA?

A

Genetic information nondiscrimination act (2008)

protects Americans from discrimination based on genetic information in health insurance and employment