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

Midterm Exam (Lectures 1-8) Flashcards

(78 cards)

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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
What dual task does the liver perform regarding metabolism?
1. metabolize substances absorbed by the gut | 2. metabolize substances already in the peripheral circulation
26
From what 2 sources does the liver receive its blood supply?
1. hepatic artery (30%) | 2. portal vein (70%)
27
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
D
28
Which non-parenchymal cell are the fat storing cells, which are natural killer lymphocyte cells, and which are the macrophages of the liver?
Kupffer cells - macrophages of liver Ito cells - fat-storing cells Pit cells - natural killer lymphocytes
29
What is the main functional unit of the liver?
hepatocytes
30
Which liver surface is specialized for exchange of metabolites with blood?
basal surface
31
Which liver surface is specialized in intercellular adhesion and communication?
lateral surface
32
Which liver surface is is an ATP-dependent export carrier
apical surface
33
What area of the liver do hepatocytes actively consume O2?
periportal zone
34
Which liver zone would have a reduced O2 content and increased concentration of metabolic products?
perivenous zone
35
Which liver zone is rich in mitochondria, has the highest concentration of O2?
periportal zone
36
True or False - hepatocytes and nonparenchymal cells display marked heterogeneity in morphology, proliferative potential, and biochemistry and functions?
True
37
Cells in which liver zone have a bigger proliferative potential and smaller cells?
Periportal zone
38
Which liver zone contains the most CYP450 expression? What are the toxicological implications of zonal expression of DME (drug metabolizing enzymes)?
Perivenous zone Oxidative activation of hepatotoxic drugs by CYP450 in the PV zone, obviously will damage the PV zone
39
What compound, metabolized by alcohol dehydrogenase, damages the PP zone and not the PV zone?
allyl alcohol
40
What is used to measure CYP450 activity?
microsomal fraction
41
What effect does lipophilicity have on renal clearance of drug metabolite?
increased lipophilicity means the drug metabolite is less easily excreted
42
What effect does glucuronidation have on the lipophilicity of a drug?
That drug's metabolite would be more hydrophilic and less lipophilic and thus more easily cleared via kidneys
43
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?
False - it's the opposite Portal vein - delivers food, drug, toxins, and recycled bile salts Hepatic artery - delivers oxygen, nutrients, and circulating drug
44
What 3 things does each hexagon-shaped liver lobule contain?
1. hepatocytes 2. vascular supply 3. biliary system
45
Where is UGT (Glucuronosyltransferase) metabolic enzyme located? Where is GST and SULT metabolic enzymes located?
UGT = INSIDE the ER (endoplasmic reticulum) - responsible for glucuronidation GST & SULT = in cytosol
46
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?
2 Water is the source of protons O2 comes from air
47
True or False - simultaneous binding of more than one substrate within the active site can lead to homotropic and heterotropic cooperatively in P450's?
True
48
Defects in which enzyme isoform are associated with degenerative arthritis syndrome?
PAPS2
49
When separating proteins by molecular mass, which size protein would move faster across the field?
smaller size proteins move faster and larger proteins move slower
50
What kind of peptide is glutathione (GSH)?
Tripeptide
51
The elimination of LIPOPHILIC molecules via metabolic transformation occurs in what?
the smooth endoplasmic reticulum (SER) where CYP450s are located
52
Which CYP enzyme is most abundant in human liver?
CYP3A4
53
Human genome contains _______ CYP genes?
57
54
Which CYP subfamily metabolizes about 50% of all drugs? Which CYP subfamily metabolizes the next largest amount?
CYP3A CYP2D
55
True or False - the same drug can be oxidized by different isoforms of CyP450?
True
56
What is the largest capacity Phase II clearance system?
Glucuronidation
57
What set of enzymes is responsible for glucuronidation?
UDP-Glucuronosyl Transferases (UGT) - conjugates glucuronic acid to lipophilic molecules
58
Where is the greatest concentration of UGT in the human body (HINT: be specific)?
liver, inside the SER
59
True or False - glucuronidation is a major route of clearance for exogenous environmental pollutants?
True
60
What is the cofactor involved in glucuronidation?
UDPGA R-OH + UDPGA --> catalyzed by UGT --> R-glucuronide conjugate
61
How are glucuronides excreted from body?
in urine and bile
62
Name the (6) substrates for UGT?
1. aliphatic alcohols 2. phenols 3. carboxylic acids 4. amines 5. thiols 6. acidic carbons
63
What is the major site of conjugation for sulfating reactions?
hydroxyl groups
64
Biochemical sulfation is accomplished by a family of enzymes known as?
sulfotransferases
65
In what 2 locations are sulfotransferases located (HINT: be specific)?
1. cytosol | 2. golgi apparatus
66
True or False - SULTs are extremely important in steroid metabolism?
True - SULT2 = steriod sulfation
67
Which SULT family is the "drug metabolizing SULT" and which SULT family is not involved in drug metabolism?
Cytosolic SULT = drug metabolizing SULT Golgi SULT = not involved in drug metabolism
68
What is the major xenobiotic SULT in human liver?
SULT1A1
69
True or False - SULT1A3 is unique for humans?
True
70
True or False - SULT1E1 is a dimer and responsible for sulfation of beta-estradiol?
True
71
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
Immunoblot analysis (Western analysis)
72
Which SULT is the brain-selective SULT
SULT4A1
73
True or False - glutathione S-transferases (GSTs) have a broad substrate specificity?
True
74
Interaction with polypeptide chain of GST makes glutathione _______(more/less) reactive?
More reactive
75
True or False - GSH conjugates need energy for excretion?
True - Excreted by ATP-dependent transporters
76
What are GSH conjugates often processed to before excretion with urine or bile?
mercapturic acid
77
________(increased/decreased) levels of GST contribute to tumor resistance to chemotherapy?
Increased levels of GST - tumors that product increased [GST] develop drug resistance
78
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 ```
F

Pharmacogenomics (5 decks)

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