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Biochemistry > Xenobiotics > Flashcards

Xenobiotics Flashcards

1
Q

Compound that is foreign to the body

Compounds in plant food, and synthetic compound in medicines, food additives, and environmental pollutants

A

Xenobiotics

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2
Q

Drugs
Chemical carcinogens
Various compounds

that have found their way into our environment like PCB’s and insecticides

A

Xenobiotics

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3
Q

Xenobiotics are metabolized or excreted

A

unchanged

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4
Q

Xenobiotics biologic effects:

A

Pharmacologic responses
Toxicity
Immunologic reactions
Cancer

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5
Q

Phase 1 of Xenobiotic Metabolism

Main reaction involved

A

Hydroxylation

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6
Q

Phase 1 is catalyzed by

A

CYP 450

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7
Q 
Deamination
Dehalogenation
Desulfuration
Epoxidation
Peroxygenation
Reduction
A

Phase 1

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8
Q

To increase water solubility (polarity) and thus excretion from the body

A

Purpose of the 2nd phase of metabolism

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9
Q

Persist in adipose tissue indefinitely

A

Very hydrophobic xenobiotics

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10
Q 
Conjugation with glucoronic acid
Sulfate
Acetate
Glutathione
Certain amino acids
Methylation
Catalyzes by enzymes such as glucuronosyltransferases, sulfotransfersases, glutathione s-transferases using UDP-glucoronic acid, PAPS (active sulfate) and glutathione respectively as donors
A

Phase 2

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11
Q

Xenobiotics are metabolized mainly in the

A

liver

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12
Q

Convert the parent drug to a more polar metabolite (active or inactive)

A

Phase 1 reaction

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13
Q

Endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate

A

Phase II reactions

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14
Q

A nonpolar drug absorbed goes into

A

Phase 1

Modified metabolite
Inactive metabolite

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15
Q

Hydrophilic drugs goes straight to

A

Excretion or elimination

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16
Q

A slightly polar drug goes to

A

Phase 2

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17
Q

59/M, Stroke
Aspirin
Clopidogrel
Atorvastatin

Occasional epigastric pain when taking these drugs

Which is discouraged to be given to this patient?

a. Ranitidine
b. Omeprazole
c. Pantoprazole
d. Lansoprazole

A

B

both metabolized by CYP219

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18
Q

Addition of functional group OH

A

Hydroxylation

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19
Q

Enzymes monooxygenase CYP 450 is found in vesicles called

A

Microsomes

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20
Q

Cytochromes have the metal complex

A

Iron

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21
Q

Drug combines with oxidixed FE3+ form of ion in CYP450 becoming a

A

binary complex

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22
Q

NADPH donates electron to the flavoprotein to reduce the oxidized P450 complex by

A

P450 reductase

Fe 3+ becomes Fe 2+ (reduced)

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23
Q

A second electron from NADPH will serve to reduce oxygen becoming

A

activated oxygen-P450 complex

P450Fe2+O2

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24
Q

P450Fe2+O2 complex transfers oxygen to

A

the drug metabolized forming an oxidized product + H20 from other O atom

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25
Q

From CYP450 drug is released in

A

hydroxylated form

addition of OH

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26
Q

Drug substrates that undergo aromatic hydroxylations

A 
Propranolol
Phenobarbital
Phenytoin
Amphetamine
Warfarin
17alpha-ethinyl estradiol 
Napthalene
Phenylbutazone
Acetalinide  
Benzpyrene
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27
Q

Drug substrates that undergo aliphatic hydroxylations

A 
Amobarbital
Pentobarbital
Secobarbital
Chlorpropamide
IBUPROFEN
meprobamate
Glutethimide
Phenylbutazone
DIGITOXIN
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28
Q

Drug that undergoes epoxidation

A

Aldrin

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29
Q

Drug substrates that undergo N-Dealkylation

O-Dealkylation

A 
Morphine
Ethylmorphine
Benzphetamine
Aminopyrine
CAFFEINE
THEOPHYLLINE
CODEINE
p-nitroanisole
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30
Q

Drug substrates that undergo S-Dealkylation

A

6-Methylthiopurine

Methitural

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31
Q

The only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as subtrates in Phase 1 is their

A

High lipid solubility

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32
Q

P450s are remarkably

A

sluggish catalyst

hence need for second phase reactions

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33
Q

Greatest in liver cells and enterocytes

A

CYP450 Family

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34
Q

CYP450 in the liver is found in the

A

endoplasmic reticulum

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35
Q

CYP450 in the adrenal gland is found in the

A

ER

Mitochondria

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36
Q

Main pathway of nicotine metabolism
Accounts for 70-80%

Coumarin, tobacco nitrosamines
Nicotine

A

Cytochrome 2A6

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37
Q

Nicotine is degraded by C2A6 to

A

Cotinine

2’ hydroxynicotine

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38
Q

Cytochrome that metabolizes

Diazepam
S-mephenytoin
Naproxen
Nirvanol
Omeprazole
Clopidogrel
Propranolol
A

CYP2C19

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39
Q

Cytochrome that metabolized

Warfarin
Acetaminophen 
Caffeine
Clomipramine 
Duloxetene
Melatonin
Tamoxifen
Theophylline
A

CYP1A2

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40
Q

Pharmacologic interaction between omeprazole and clopidogrel leads to

A

Significantly reduced exposure of active metabolite of clopidogrel

Reduction in anticlotting activity of Clopidogrel

At risk for stroke and MI

bec they utilize the same CYP2C19 pathway

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41
Q

Metabolizes the following drugs

Celecoxib
Diclofenac
Ibuprofen
Losartan

A

CYP2C9

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42
Q

This cytochrome is responsible for over 50% of the prescription drugs metabolized in the liver

A

Cytochrome 3A4

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43
Q

Which of the following will increase the metabolism of Warfarin?

a. Grapefruit juice
b. Ketoconazole
c. Isoniazid
d. Rifampin

A

D

44
Q

Increases the metabolism of drugs on repeated administration

Induces P450 by enhancing its synthesis

Accelerated substrate mechanism

Decreases drug efficacy

Dose must be increased

A

Inducer

45
Q

OCPs have decreased efficacy with concomittant use of

A

Rifampin

Both decreased efficacy

46
Q

Benzopyrene (barbecue) induces

A

Theophylline

47
Q

Carbamazepine induces

A

Clonazepam,

Itraconazole

48
Q

Chlorcyclizine induces

A

Steroid hormones

49
Q

Ethchlorvynol induces

A

Warfarin

50
Q

Griseofulvin induces

A

Warfarin

51
Q

Phenytoin induces

A 
Cortisol
Dexamethasone
Digitoxin
Itraconazole
Theophylline
52
Q

Rifampin is induces

A 
Coumarin
Digitoxin
Glucocorticoids
Itraconazole
Methadone
Metoprolol
OCP
Prednisone
Propranolol
Quinidine
Saquinavir
53
Q

Ritonavir is induces

A

Midazolam

54
Q

St John’s Wort induces

A 
Alprazolam
Cyclosporin
Digoxin
Indinavir
OCP
Ritonavir
Simvastatin
Tacrolimus
Warfarin
55
Q

A susbtance that binds to CYP450 and decreases its activity

Decreased metabolism of the drug

Increased drug efficacy

Dose must be decreased

A

Inhibitor

56
Q

Increases efficacy of valium (diazepam) and may increase its toxic effects

inhibitor

A

Alcohol

57
Q

Allopurinol
Chloramphenicol
Isoniazid

inhibits

A

Antipyrene
Dicumarol
Probenecid
Tolbutamide

58
Q

Chlorpromazine inhibits

A

Propranolol

59
Q

Cimetidine inhibits

A

Chlordiazepoxide
Diazepam
Warfarin

60
Q

Dicumarol inhibits

A

Phenytoin

61
Q

Disulfiram inhibits

A

Antipyrine
Ethanol
Phenytoin
Warfarin

62
Q

Ethanol inhibits

A

Chlordiazepoxide
Diazepam
Methanol

63
Q

Grapefruit juice inhibits

A 
Alprazolam
Atorvastatin
Cisapride
Cyclosporine
Midazolam
Triazolam
64
Q

Itraconazole inhibits

A 
Alfentanil
Alprazolam
Atorvastatin
Cyclosporine
Diazepam 
Digoxin
65
Q

OCP inhibit

A

Antipyrine

66
Q

Ketoconazole inhibits

A

Astemizole
Cyclosporine
Terfenadine

67
Q

Spironolactone inhibits

A

Digoxin

68
Q

Most frequent conjugation reaction of Phase II

A

Glucoronidation

ex. bilirubin

69
Q

Enzyme responsible for glucoronidation

Present in the cytosol and ER

A

Glucoronosyltransferases

70
Q

Acetylation involves the enzyme

A

N-acetyltransferase in cytosol

71
Q

Acetaminophen undergoes this type of Phase II Conjugation

A

Glucoronidation

Morphine
Diazepam
N-hydroxydapsone
Digitoxin 
Digoxin
72
Q

Isoniazid
Sulfonamide
Clonazepam
Dapsone

undergoes this type of Phase II conjugation

A

acetylation

73
Q

Acetaminophen
Ethacrynic acid
Bromobenzene

undergoes this type of Phase II conjugation

A

Glutathione conjugation

74
Q

Glutathione conjugation occurs via the enzyme

A

GSH-S transferase (cytosol, microsome)

75
Q

Acetaminophen undergoes the ff Phase II reactions

A

Glucurononidation (95%)
Glutathione conjugation (5%)
Sulfation (95%)

76
Q

Dopamine, epinephrine and histsmine undergoes this Phase II conjugation

A

Methylation by transmethylase SAM

77
Q

Leukotriene A4 undergoes this type of Phase II conjugation

A

Water conjugation

78
Q

Therapeutic dose of Acetaminophen in adult

A

3 g

79
Q

When acetaminophen undergoes glutathione conjugation pathway by CYP2E1 and CYP3A4, GSH is depleted faster than it can be regenated and this metabolite accumulates

A

N-acetylbenzoiminoquinone

80
Q

If GSH is able to bind to N-acetylbenzoiminoquinone, no toxic metabolite accumulates and this persists instead

A

Mercapturic acid conjugate

81
Q

N-acetylbenzoiminoquinone binding with Nucleophilic Cell Macromolecule (Protein-SH) leads to

Redox recycling, ROS generation, oxidative stress

A

Liver cell death

82
Q

Antidote for paracetamol toxicity in 8-16 hours

A

N-acetylcysteine

83
Q

Administration of GSH is not effective in acetaminophen toxicity because

A

it does not cross cell membranes readily

84
Q

Bacterially mediated reduction of digoxin

De-glucoronidation of bile

A

Commensal Gut Microbiota

85
Q

Charcoal-broiled foods and cruciferous vegetables: induce CYP1A enzymes

Grapefruit juice inhibits CYP3

Cigarette smoke: enzyme induction

A

Diet and environmental factors

86
Q

Slower metabolism: very young and very old

Young adult male rats metabolize drugs much faster

A

Age and Sex

87
Q

Digoxin is reduced in the gut by

A

Bacteria

88
Q

Charbroiled foods and cruciferous vegetables induce

A

CYP1A

89
Q

Grapefruit inhibits

A

CYP3A

90
Q

Cigarette is an enzyme

A

Inducer

91
Q

Bound to active site and ER

Induce microsomal enzymes

A

Lipophilic substrates

92
Q

May enhance also its own metabolism leading to tolerance

A

Inducer

93
Q

Some drugs require conjugation with endogenous substrates such as GSH, glucuronic acid or sulfate for their inactivation

Faster-reacting drug may effectively deplete endogenous substrate levels

A

Drug-Endogenous Substance Interactions

94
Q

Cirrhosis
Hepatitis
Biliary cirrhosis

A

Affect drug metabolism

Impair hepatic enzymes and drug elimination

95
Q

Cardiac disease limits blood flow to liver hence impairs liver metabolism of drugs such as

A

Lidocaine
Isoniazid
Morphine

96
Q

Pulmonary diseases affect drug metabolism as indicated by impaired hydrolysis of

and increased half life of

A

Procainamide
Procain

Antipyrin in lung cancer

97
Q

Endocrine dysfunction on drug metabolism

Thyroid dysfunction has been associated with altered metabolism of

A

Digoxin
Methimazole

Increased half life

98
Q

Cytokine mediators impair drug metabolism by

A

inactivating CYP450

enhancing their degradation

99
Q

Variant allele of a gene at a population frequency of >/= 1%

First drugs -> succinylcholine, INH, warfarin

Adverse drug reactions -> dose adjustments needed

A

Genetic polymorphism

100
Q

Genetic variants of enzymes in phase I
CYP2C19

Individuals with variant allele for CYP2C19 exhibit increased metabolism of Omeprazole and Clopidogrel

Increase dose of the drugs

A

Phase I Polymorphism

101
Q

Nicotine oxidation is through

A

CYP2A6 activity

102
Q

If patient has CYP2A6 polymorphism they are

A

Less prone to lung cancer even if smoker

103
Q

Butyrylcholinesterase deficiency (BCHE)

Succinylcholine

A

Phase II Polymorphism

104
Q

Slow acetylator phenotype NAT2

Common in 50% of blacks

Given isoniazid, patient will be prone to developing isoniazid induced periphera neuritis, autoimmune diseases, bladder cancer

A

Phase II

Polymorphism

105
Q

UGT Polymorphism

UGT1A128
Hyperbilirubinemic diseases
(Gilbert’s syndrome)

Toxic effects due to impaired drug conjugation or elimination such as irinotectan for patients with cancer

A

Phase II

Polymorphism

106
Q

Phase II Polymorphism

A

Butyrylcholinesterase
Slow acetylator Phenotype NAT2
UGT Polymorphism

Biochemistry (32 decks)

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