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Pharmacogenomics > Midterm Exam (Lectures 1-8) > Flashcards

Midterm Exam (Lectures 1-8) Flashcards

1
Q

What are the 3 classes of polypeptides involved in PGx?

A
  1. drug metabolizing enzymes
  2. drug transporters
  3. drug targets
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2
Q

Application of PGx in daily clinical practice is limited by:

A) complex inheritance patterns
B) limited therapeutic options
C) lack of PGx training
D) All of the above

A

D

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3
Q

True or False - as of 2003, no new drug can be submitted for approval without submitting PGx data?

A

True

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4
Q

According to the FDA PGx guidance, what are the 2 valid biomarkers?

A
  1. Cytochrome P450 2D6 (CYP2D6 & CYP2C19)

2. Thiopurine S-methyltransferases (TPMT)

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5
Q

What PK property determines the therapeutic outcome of the drug treatment?

A

metabolism

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6
Q

Metabolism changes the drug. Can metabolism also change the concentration and distribution of the drug?

A

Yes

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7
Q

What are the 2 outcomes of a drug being metabolized?

A
  1. detoxification for removal from body

2. incorporation into biosynthetic pathways

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8
Q

Of the 70% of the top 200 drugs (140 drugs), what % are metabolized by Phase 1 metabolism and what % by Phase 2 metabolism?

A

Phase 1 - 70% (CYP 450’s)

Phase 2 - 15% (UDPG)

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9
Q

Insertion of a chemically active functional group describes what type of metabolism?

A

Phase 1 metabolism

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10
Q

True or False - all the following are examples of Phase 1 metabolism:

aromatic hydroxylation
aliphatic hydroxylation
dealkylation
oxidative deamination
S-oxidation
dehalogenation
A

True

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11
Q

A deficiency in this enzyme results in Fish Odor Syndrome where patient is unable to N-oxidize trimethylamine?

A

FMO3 (FAD-containing Monooxygenase)

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12
Q

How many families and subfamilies of CYP450 genes do humans have?

A

18 families

43 subfamilies

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13
Q

What are the 2 mechanisms for broad substrate specificity of oxidative metabolism by CYP 450?

A
  1. CYP450 generate highly reactive oxidative species able to oxidize almost any C-H bond
  2. CYP450 is a family of proteins with overlapping substrate specificity
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14
Q

True or False - Phase 2 metabolism is often used as an active (high-energy) co-factor?

A

True

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15
Q

True or False - The final products of Phase 2 metabolism are highly soluble in water?

A

True

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16
Q

Fill in the BLANKS:

Phase 2 metabolism results in _________ hydrophilicity and ___________ lipophilicity?

A

Increased hydrophilicity

Decreased lipophilicity

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17
Q

True or False - Phase 2 metabolizing enzymes generate highly reactive species and have multiple isoforms with overlapping substrate specificity?

A

True

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18
Q

What is the major conjugation pathway for phenols?

A

Sulfation

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19
Q

What is the energy-rich donor source of sulfo group in sulfation conjugation (phase 2 metabolism)?

A

PAPS

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20
Q

What is the energy-rich cofactor source of methyl group in methylation?

A

S-adenosylmethionine

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21
Q

Where does acetylation occur?

A

in Kupffer cells in the liver

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22
Q

What is the energy-rich substrate source for acetylation?

A

Acetyl-CoA

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23
Q

True or False - most drug labels provide PGx information with NO immediate recommendation for a specific action (i.e. genetic testing)?

A

True

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24
Q

Name the 6 drug-metabolizing tissues in the body?

A
  1. liver (major site)
  2. lung
  3. kidney
  4. skin
  5. intestinal mucosa
  6. placenta
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25
Q

What dual task does the liver perform regarding metabolism?

A
  1. metabolize substances absorbed by the gut

2. metabolize substances already in the peripheral circulation

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26
Q

From what 2 sources does the liver receive its blood supply?

A
  1. hepatic artery (30%)

2. portal vein (70%)

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27
Q

Which of the following are non-parenchymal cells (sinusoidal endothelial cells) of the liver:

A) Kupffer cells
B) Ito cells
C) Pit cells
D) all of the above

A

D

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28
Q

Which non-parenchymal cell are the fat storing cells, which are natural killer lymphocyte cells, and which are the macrophages of the liver?

A

Kupffer cells - macrophages of liver
Ito cells - fat-storing cells
Pit cells - natural killer lymphocytes

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29
Q

What is the main functional unit of the liver?

A

hepatocytes

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30
Q

Which liver surface is specialized for exchange of metabolites with blood?

A

basal surface

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31
Q

Which liver surface is specialized in intercellular adhesion and communication?

A

lateral surface

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32
Q

Which liver surface is is an ATP-dependent export carrier

A

apical surface

33
Q

What area of the liver do hepatocytes actively consume O2?

A

periportal zone

34
Q

Which liver zone would have a reduced O2 content and increased concentration of metabolic products?

A

perivenous zone

35
Q

Which liver zone is rich in mitochondria, has the highest concentration of O2?

A

periportal zone

36
Q

True or False - hepatocytes and nonparenchymal cells display marked heterogeneity in morphology, proliferative potential, and biochemistry and functions?

A

True

37
Q

Cells in which liver zone have a bigger proliferative potential and smaller cells?

A

Periportal zone

38
Q

Which liver zone contains the most CYP450 expression? What are the toxicological implications of zonal expression of DME (drug metabolizing enzymes)?

A

Perivenous zone

Oxidative activation of hepatotoxic drugs by CYP450 in the PV zone, obviously will damage the PV zone

39
Q

What compound, metabolized by alcohol dehydrogenase, damages the PP zone and not the PV zone?

A

allyl alcohol

40
Q

What is used to measure CYP450 activity?

A

microsomal fraction

41
Q

What effect does lipophilicity have on renal clearance of drug metabolite?

A

increased lipophilicity means the drug metabolite is less easily excreted

42
Q

What effect does glucuronidation have on the lipophilicity of a drug?

A

That drug’s metabolite would be more hydrophilic and less lipophilic and thus more easily cleared via kidneys

43
Q

True or False - the portal vein delivers oxygen, nutrients, and circulating drug to the liver hepatocytes while the hepatic artery delivers food, drug, toxins, and recycled bile salts?

A

False - it’s the opposite

Portal vein - delivers food, drug, toxins, and recycled bile salts

Hepatic artery - delivers oxygen, nutrients, and circulating drug

44
Q

What 3 things does each hexagon-shaped liver lobule contain?

A
  1. hepatocytes
  2. vascular supply
  3. biliary system
45
Q

Where is UGT (Glucuronosyltransferase) metabolic enzyme located? Where is GST and SULT metabolic enzymes located?

A

UGT = INSIDE the ER (endoplasmic reticulum) - responsible for glucuronidation

GST & SULT = in cytosol

46
Q

The catalytic cycle of CYP450’s involves the addition of how many electrons? What is the role of water in this catalytic cycle? Where do the O2 atoms come from?

A

2

Water is the source of protons

O2 comes from air

47
Q

True or False - simultaneous binding of more than one substrate within the active site can lead to homotropic and heterotropic cooperatively in P450’s?

A

True

48
Q

Defects in which enzyme isoform are associated with degenerative arthritis syndrome?

A

PAPS2

49
Q

When separating proteins by molecular mass, which size protein would move faster across the field?

A

smaller size proteins move faster and larger proteins move slower

50
Q

What kind of peptide is glutathione (GSH)?

A

Tripeptide

51
Q

The elimination of LIPOPHILIC molecules via metabolic transformation occurs in what?

A

the smooth endoplasmic reticulum (SER) where CYP450s are located

52
Q

Which CYP enzyme is most abundant in human liver?

A

CYP3A4

53
Q

Human genome contains _______ CYP genes?

A

57

54
Q

Which CYP subfamily metabolizes about 50% of all drugs? Which CYP subfamily metabolizes the next largest amount?

A

CYP3A

CYP2D

55
Q

True or False - the same drug can be oxidized by different isoforms of CyP450?

A

True

56
Q

What is the largest capacity Phase II clearance system?

A

Glucuronidation

57
Q

What set of enzymes is responsible for glucuronidation?

A

UDP-Glucuronosyl Transferases (UGT) - conjugates glucuronic acid to lipophilic molecules

58
Q

Where is the greatest concentration of UGT in the human body (HINT: be specific)?

A

liver, inside the SER

59
Q

True or False - glucuronidation is a major route of clearance for exogenous environmental pollutants?

A

True

60
Q

What is the cofactor involved in glucuronidation?

A

UDPGA

R-OH + UDPGA –> catalyzed by UGT –> R-glucuronide conjugate

61
Q

How are glucuronides excreted from body?

A

in urine and bile

62
Q

Name the (6) substrates for UGT?

A
  1. aliphatic alcohols
  2. phenols
  3. carboxylic acids
  4. amines
  5. thiols
  6. acidic carbons
63
Q

What is the major site of conjugation for sulfating reactions?

A

hydroxyl groups

64
Q

Biochemical sulfation is accomplished by a family of enzymes known as?

A

sulfotransferases

65
Q

In what 2 locations are sulfotransferases located (HINT: be specific)?

A
  1. cytosol

2. golgi apparatus

66
Q

True or False - SULTs are extremely important in steroid metabolism?

A

True - SULT2 = steriod sulfation

67
Q

Which SULT family is the “drug metabolizing SULT” and which SULT family is not involved in drug metabolism?

A

Cytosolic SULT = drug metabolizing SULT

Golgi SULT = not involved in drug metabolism

68
Q

What is the major xenobiotic SULT in human liver?

A

SULT1A1

69
Q

True or False - SULT1A3 is unique for humans?

A

True

70
Q

True or False - SULT1E1 is a dimer and responsible for sulfation of beta-estradiol?

A

True

71
Q

These 3 steps describe what kind of analysis?

  1. separation of proteins in the gel
  2. transfer of proteins on a membrane
  3. detection of specific proteins with antibody
A

Immunoblot analysis (Western analysis)

72
Q

Which SULT is the brain-selective SULT

A

SULT4A1

73
Q

True or False - glutathione S-transferases (GSTs) have a broad substrate specificity?

A

True

74
Q

Interaction with polypeptide chain of GST makes glutathione _______(more/less) reactive?

A

More reactive

75
Q

True or False - GSH conjugates need energy for excretion?

A

True - Excreted by ATP-dependent transporters

76
Q

What are GSH conjugates often processed to before excretion with urine or bile?

A

mercapturic acid

77
Q

________(increased/decreased) levels of GST contribute to tumor resistance to chemotherapy?

A

Increased levels of GST - tumors that product increased [GST] develop drug resistance

78
Q

GSTs are relevant to all of the following except:

A) inflammation
B) drug development
C) drug resistance
D) anti-carcinogenesis
E) antibiotic resistance
F) relevant to all
A

F

Pharmacogenomics (5 decks)

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