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Pharmacogenomics > Final Exam (Lecture 17 - 21) > Flashcards

Final Exam (Lecture 17 - 21) Flashcards

1
Q

Which of the following statements regarding NAT are correct?

A. transfers acetate from Acetyl-CoA to primary aromatic amines and hydrazines
B. Membrane bound enzymes
C. Only present in eukaryotes
D. Isoniazid and sulfometazin are polymorphic substrates of NAT
E. Only A & D

A

(E) Only A & D are correct - polymorphic substrate of NAT means that there are fast and slow metabolizers of that substrate (drug). A monomorphic substrate means that everyone metabolizes it at the same rate.

  • B - NAT is a cytosolic enzyme, not membrane bound
  • C - present in eukaryotes AND prokaryotes
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2
Q

Which of the following statements is incorrect?

A. p-Aminosalcylate is metabolized at identical rates
B. NAT1 metabolizes monomorphic substrates while NAT2 metabolizes polymorphic substrates
C. PNAT does not code for any proteins
D. NAT2 is a phase 2 drug metabolizing enzyme
E. Caffeine test cannot determine acetylation capacity of patients

A

(E) Caffeine test CAN determine acetylation capacity of patients. Test involves giving patient caffeine, collecting urine, and analyzing using HPLC (high pressure liquid chromatography)

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3
Q

All of the following are NAT1 substrates, except?

A. p-aminobenzoylglutamate
B. PABA
C. p-aminosalicylic acid
D. Caffeine
E. All of the above are NAT1 substrates
A

(D) Caffeine is a NAT2 substrate

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4
Q

All of the following are NAT2 substrates, except?

A. Amonafide
B. Caffeine
C. Dapsone
D. Hydralazine
E. All of the above are NAT2 substrates
A

(E) all of the above

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5
Q

What food derived heterocyclic amine is converted to a DNA-reactive form (carcinogen) catalyzed by NAT2?

A

PhIP - most abundant heterocyclic amine carcinogen in the human diet

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6
Q

NAT2 Substrates

A
  1. Isoniazid
  2. hydralazine
  3. sulfamethazine
  4. procainamide
  5. clonazepam
  6. dapsone
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7
Q

Which of the following statements is incorrect?

A. NAT2 inactivates isoniazid (TB drug)
B. NAT14 wild type and NAT24 wild type are associated with slow acetylator phenotype
C. PNAT is a psuedogene
D. NAT1 and NAT2 share 87% nucleotide and 81% aa identity
E. 3 NAT loci located on chromosome 8

A

(B) NAT14 wild type and NAT24 wild type is associated with FAST acetylator phenotype

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8
Q

True or False - NAT2*4 wild type rapid metabolizer is the most frequent genetic variant in caucasian populations (in NAT family)

A

True

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9
Q

True or False - there is a possible relationship between slow NAT2 phenotype and urinary bladder cancer?

A

True

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10
Q

NATs have been identified in all the following species, except?

A. human
B. rabbit
C. mycobaterium
D. dog
E. chicken
A

(D) NATs are NOT in dogs

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11
Q

A traditional approach to a drug metabolism study based on animal models is not universal for which of the following reasons?

A. interspecies variations in drug metabolism
B. regulation patterns in humans and animals
C. substrate specificity of enzymes and species-species isoforms
D. Only A & B
E. All of the above

A

(E) all of the above

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12
Q

Which of the following statements is incorrect?

A. rabbits are not a good animal to study steroidal sulfation
B. Imipramine is metabolized by CYP enzymes
C. N-demethylation catalyzed by 1A2 and 3A4 is the major metabolic pathway of Imipramine
D. 2D6 catalyzes 2-hydroxylation of Imipramine
E. none of the above

A

(E) none of the above are incorrect

*B - CYP’s hydroxylate (add -OH) and demethylate

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13
Q

Drug metabolism studies with human tissues are not universal for which of the following reasons?

A. inter-individual variations exist
B. inherited factors are involved
C. rare and mutant isoforms are difficult to study
D. Only A & B
E. all of the above
A

(E) all of the above

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14
Q

Which of the following major classes of drug metabolizing enzymes (DME) is incorrectly matched to the number of isoforms in each class?

A. CYP450 - 67
B. UDP glucuronosyl transferases - 20
C. Sulfotransferases - 11
D. Glutathione S-transferases - 16
E. None of the above
A

CYP450 has 57 different isoforms, not 67

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15
Q

All of the following DME are located in the cytosol, except?

A. NAT
B. GST
C. SULT
D. UGT
E. All of the above located in cytosol
A

(D) UGT is located in the endoplasmic reticulum (ER) lumen

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16
Q

What is a common selective CYP probe substrate for 2C9?

A

Diclofenac 4-hydroxylation

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17
Q

True or False - HPLC determines the chemical composition of mixture (especially important in metabolites)

A

True

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18
Q

Which of the following statements is correct?

A. HPLC involves multiple metabolites moving through a column at different speeds and physically separating
B. CYP2D6 is NOT inducible

A

*B - CYP2D6 is not inducible but can be inhibited (ex. quinidine)

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19
Q

Which CYP does Furafyline inhibit?

A

1A2

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20
Q

Which CYP does Sulfaphenazole inhibit?

A

2C9

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21
Q

Which CYP does Benzyl nirvanol inhibit?

A

2C19

22
Q

Which CYP does Quinidine inhibit?

A

2D6

23
Q

Which CYP does Ketoconazol inhibit?

A

3A4/5

24
Q

True or False - CYP2D6 can be induced by rifampin?

A

False - 2D6 is NOT inducible

25
Q

What 2 clinically relevant CYP enzymes are induced by rifampin and phenobarbitone?

A

2C9 & 3A4

26
Q

Which of the following are transgenic organisms for drug metabolism study?

A. bacteria
B. lower eukaryotes
C. mammalian cells
D. animals (humanized and knockout mice)
E. all of the above
A

(E) all of the above

27
Q

Which of the following statements about CYP450 enzymes is correct?

A. superfamily of hemoproteins
B. metabolizes xenobiotics and endogenous compounds
C. 50% of drugs metabolized by 2D6
D. Only A & B
E. All of the above
A

(D) only A & B are correct

*C - 50% of drugs are metabolized by 3A4

28
Q

Which of the following statements is incorrect?

A. CYP2D6 was involved in 38% of all ADR reports
B. Efficient metabolizers have two functional alleles
C. Ultrarapid metabolizers typically have gene duplication or induction of enzymes
D. CYP2C9 has a role in inflammation and infarction
E. NSAIDs and warfarin are NOT substrates of 2C9

A

(E) NSAIDs and warfarin ARE substrates of 2C9

*Common 2C9 substrates: oral anti diabetics, NSAIDs, oral anticoagulants, angiotensin antagonists

29
Q

Which of the following about CYP2A6 is correct?

A. Contributes to smoking behavior
B. represent 10% of total liver CYP content
C. oxidizes (activates) carcinogen 1,3 buadiene
D. Only B & C
E. All of the above

A

(E) All of the above

30
Q

Name (2) drugs that induce 2A6? Name (2) drugs/foods that inhibit 2A6?

A

INDUCED by phenobarbitone and rifampin

INHIBITED by methoxalen and grapefruit juice

31
Q

Which of the following statements regarding 2C9 is correct?

A. Located on chromosome 8
B. Contains 5 introns
C. Warfarin dose must be significantly reduced in patients with allele CYP2C93/3
D. 3/3 would represent homozygous mutant
E. C & D

A

(E) C & D are correct

  • A - located on chromosome 10
  • B - contains 9 introns
32
Q

True or False - CYP2C9 metabolizes small acidic and lipophilic molecules?

A

True

33
Q

True or False - CYP2C9 interacts with one of the two stereoisomers of warfarin and ibuprofen

A

True

34
Q

Which of the following regarding CYP2C19 is incorrect?

A. located on chromosome 10
B. Asians have a relatively high % of being PM
C. metabolizes both cyclophosphamide and teniposide even though both have very different structures
D. 2C19 PMs result in better efficacy with omeprazole
E. none of the above

A

(E) none of the above are incorrect

35
Q

Which of the following drugs is CYP2C19 NOT responsible for metabolizing?

A. Diazepam
B. Omeprazole
C. Sertraline
D. Warfarin
E. C & D
A

(D) 2C19 does NOT metabolize warfarin. All others are metabolized by CYP2C19

36
Q

True or False - the most significant difference between 2C19 and 2C9 is that unlike 2C9, 2C19 does NOT oxidize acidic molecules?

A

True

37
Q

What chromosome is CYP2D6 located on?

A

chromosome 22

38
Q

Which of the following statements is correct?

A. Low affinity for alkaloids (plant toxins)
B. Debrisoquine is exclusively metabolized by CYP2D6
C. Large population in East Africa with CYP2D6 gene duplication
D. B & C
E. All of the above

A

(D) - B & C are correct

*A - CYP2D6 has a HIGH affinity for alkaloids (plant toxins)

39
Q

Which of the following statements is correct?

A. 2D6 is important in antidepressant drug therapy
B. Polymorphic 2D6 and 2C9 involved in analgesic drug metabolism
C. 3A gene locus located on chromosome 7
D. CYP3A distribution is predominantly pericentral
E. All of the above

A

(E) all of the above

*A - many antidepressant drugs are 2D6 substrates (TCA, SSRIs, etc.) not citalopram

40
Q

Which of the following regarding CYP3A4 is correct?

A. broad substrate specificity
B. 3A4 alleles do NOT contribute to polymorphic drug metabolism
C. Midazolam and Triazolam are used to measure activity of 3A4 in the liver
D. A & C
E. All of the above

A

(E) all of the above

*there are about 20 3A4 alleles that are all extremely rare with unknown functional roles

41
Q

The rate limiting step in uracil catabolism is catalyzed by what enzyme?

A

Dihydropyrimidine Dehydrogenase (DPD)

42
Q

Which of the following regarding DPD is incorrect?

A. Has 1 binding site each for FMN, FAD, and NADPH with 4 iron sulfur motifs
B. Homodimer
C. catabolism of DPD occurs at 2 different domains of the molecule
D. DPD’s highest activity is at 1pm
E. DPD’s highest activity is at 1am

A

(D) DPD activity follows a circadian rhythm and its highest activity is at 1am and its lowest activity is at 1pm

43
Q

Which of the following conditions would be seen in DPD deficiency?

A. Thymine-uraciluria
B. Epileptic conditions
C. Microcephaly
D. Mental retardation
E. All of the above
A

(E) all of the above

44
Q

What chromosome is DPYD gene, the gene that codes for DPD, on?

A

Chromosome 1

45
Q

How many exons does DPYD gene contain?

A

23 exons

46
Q

All of the following are limitations of DPD activity assays, except?

A. 2-fold difference in DPD activity due to circadian regulation
B. significant amount of tissue required
C. Catabolism of DPD occurring at 2 different domains
D. B & C
E. A & B

A

(C) Catabolism of DPD occurring at 2 different domains has nothing to do with limitations of DPD activity assays. The other two options are limitations.

47
Q

This drug is one of the most commonly used anti-neoplastic drugs prescribed to treat colon, breast, and skin cancers?

A

5-FU

48
Q

True or False - DPD is the initial and rate-limiting enzyme of catabolism of 5-FU?

A

True

49
Q

Which of the following statements is incorrect?

A. Sorivudine (SRV) can have a deadly interaction with 5-FU
B. Proband is the first affected family member who seeks medical attention for a genetic disorder
C. DPYD*2A has been correlated with DPD deficiency
D. DPYD mutant alleles are more frequently found in Asians
E. none of the above

A

(D) I made this statement up. Also this class blows.

*A - SRV is metabolized to BVU which can inactivate DPD which means more active 5-FU will be around (85% of 5-FU is normally metabolized to inactive) and cause death

50
Q

True or False - DPD is a determinant of 5-FU efficacy in tumors?

A

True - there is a correlation between low DPD activity and increased 5-FU sensitivity

Pharmacogenomics (5 decks)

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