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TOX-CD > Ch 2 - Toxicological Mechanisms > Flashcards

Ch 2 - Toxicological Mechanisms Flashcards

1
Q

A possible reason for the selective embryo/fetal toxicity of DES is… A. Higher concentrations of free DES in embryo/fetus compared to adults B. Binding to retinoic acid receptors C. Lack of placental metabolism D. All of the above

A

A. Higher concentrations of free DES in embryo/fetus compared to adults

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2
Q

Acyl glucuronides are particularly toxic to the liver because… A. They selectively interact with macrophages releasing active oxygen B. Active transport systems in the hepatocytes and bile duct system can greatly upconcentrate them C. They are resistant to glucuronidase D. They are suicide inhibitors of UGT2B7

A

B. Active transport systems in the hepatocytes and bile duct system can greatly upconcentrate them

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3
Q

The selective renal toxicity of cephaloridine over cephalothin is due to… A. Selective uptake by the organic cation transporter B. Selective inhibition of P-glycoprotein C. Selective uptake by the organic ion transporter D. Significantly less plasma protein binding of cephaloridine

A

C. Selective uptake by the organic ion transporter

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4
Q

All of the following are true of alpha-amanitin except… A. It is less orally available than phalloidin B. It inhibits RNA polymerase II C. It is transported into the hepatocyte by a bile acid transporter D. It is a mushroom toxin

A

A. It is less orally available than phalloidin

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5
Q

All of the following are true of the toxic mechanism of paraquat except… A. Lungs accumulate paraquat in an energy -dependent manner B. Its entry into the lung is assumed to be via the polyamine transport system C. Similar molecules with smaller distances between N atoms do not enter lungs as readily D. Cytotoxicity to alveolar cells is caused primarily by interference with Ca+2 channels

A

D. Cytotoxicity to alveolar cells is caused primarily by interference with Ca+2 channels

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6
Q

Enzyme induction by phenobarbital is mediated through… A. Aryl hydrocarbon receptors B. PPAR-alpha receptors C. Constitutively active receptors (CAR) D. Estrogen receptors

A

C. Constitutively active receptors (CAR)

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7
Q

CAR is downregulated by… A. Hypericum extracts B. acetominophen C. Asprin D. Proinflammatory cytokines

A

D. Proinflammatory cytokines

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8
Q

The pregnane X receptor… A. Is a cytosolic receptor B. Is involved in the induction of Cyp3A4 C. Is primarily expressed in the skin D. All of the above

A

B. Is involved in the induction of Cyp3A4

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9
Q

Xenobiotic toxicity that occurs after repair and adaptive processes are overwhelmed include all of the following except… A. Fibrosis B. Apoptosis C. Necrosis D. Carcinogenesis

A

B. Apoptosis

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10
Q

Amphipathic xeonbiotics that can become trapped in lysosomes and cause phospholipidosis include all of the following except… A. Ethylene glycol B. Aminodarone C. Amitriptyline D. Fluoxetine

A

A. Ethylene glycol

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11
Q

Which of the following parent toxicant-electrophyllic metabolite pairs is incorrect… A. Halothane-phosgene B. bromobenzine-bromobenzene 3,4 oxide C. Benzene-muconic aldehyde D. Allyl alcohol-acrolein

A

A. Halothane-phosgene

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12
Q

All of the following are capable of accepting electrons from reductases and forming radicals except… A. Paraquat B. Doxorubicin C. N-hexane D. Nitrofurantoin

A

C. N-hexane

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13
Q

An example of the formation of an electrophile toxicant from an inorganic chemical is… A. CO to CO2 B. AsO4-3 to AsO3-2 C. NO to NO2 D. OH to H2O

A

B. AsO4-3 to AsO3-2

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14
Q

The general mechanism for the detoxification of electrophiles is… A. Conjugation with glucuronic acid B. Conjugation with acetyl CoA C. Conjugation with glutathione D. Conjugation with sulfate

A

C. Conjugation with glutathione

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15
Q

The most common nucleophilic detoxication reaction that amines undergo is… A. Acetylation B. Sulfation C. Methylation D. Amino acid conjugation

A

A. Acetylation

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16
Q

Detoxication mechanisms may fail because… A. Toxicants may overwhelm the detoxication mechanims B. Reactive toxicants may inactivate a detoxicating enzyme C. Detoxication may produce a toxic by-product D. All of the above

A

D. All of the above

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17
Q

The most potent carcinogen derived from nicotine is… A. Napthene B. Styrene C. Nicotine-derived nitrosamine ketone (NNK) D. Methyl tert-butyl ketone

A

C. Nicotine-derived nitrosamine ketone (NNK)

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18
Q

Hydroxyl radicals can be produced by all of the following except… A. The action of nitric oxide synthase on water B. Interaction of ionizing radiation and water C. Reductive homolytic fission of hydrogen peroxide D. Interaction with silica with surface iron ions in lung tissue

A

A. The action of nitric oxide synthase on water

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19
Q

If an electrophile is covalently bound to a protein that does not play a critical function, the result is considered a… A. Toxication reaction B. Detoxication reaction C. DNA adduct formation D. Fenton reaction

A

B. Detoxication reaction

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20
Q

Which of the following receptor-exogenous ligand pairs is incorrect? A. Estrogen receptor-zeralenone B. Glucocorticoid receptor - dexamethasone C. Aryl hydrocarbon receptor - rifampicin D. PPAR - clofibrate

A

C. Aryl hydrocarbon receptor - rifampicin

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21
Q

Which of the following receptor-agonist pairs is incorrect? A. Glutamate receptor - kainate B. Glycine receptor - strychnine C. GABA (A) receptor - muscimol D. Opioid receptor - meperidine

A

B. Glycine receptor - strychnine

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22
Q

Which of the following receptor antagonist pairs is incorrect? A. Adrenergic B1 receptor - metoprolol B. Serotonin (2) receptor -ketanserin C. Glutamate receptor - ketamine D. GABA (A) receptor - avermectins

A

D. GABA (A) receptor - avermectins

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23
Q

Clonidine overdose mimics poisoning with… A. Morphine B. Cocaine C. Phencyclidine D. Amphetamine

A

A. Morphine

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24
Q

All of the following act as inhibitors of the citric acid cycle except… A. 4-pentenoic acid B. Fluoroacetate C. DCVC D. Malonate

A

A. 4-pentenoic acid

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25
Q

All of the following are inhibitors of ADP phosphorylation except… A. Oligomycin B. DDT C. Ethanol D. N-ethylmaleimide

A

C. Ethanol

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26
Q

All of the following cause calcium influx into the cytoplasm except… A. Capsaicin B. Formate C. Domate D. Amphotericin B

A

B. Formate

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27
Q

All of the following inhibit Ca++ export from the cytoplasm except… A. Vanadate B. Methylmercury C. Bromobenzine D. Carbon tetrachloride

A

B. Methylmercury

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28
Q

Hydroxyl radical is enzymatically detoxified by.. A. Catalase B. Glutathione peroxidase C. Glutathione reductase D. None of the above

A

D. None of the above

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29
Q

Which of the following regarding cell death is true? A. Necrosis requires ATP B. Release of cytochrome c usually triggers necrosis C. Toxicants at low doses usually cause apoptosis and necrosis at higher doses D. Apoptosis is never a desirable effect

A

C. Toxicants at low doses usually cause apoptosis and necrosis at higher doses

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30
Q

Blockade of voltage-gated potassium channels has been demonstrated with all of the following except… A. Cisapride B. Lorazepam C. Terfenadine D. Grepafloxacin

A

B. Lorazepam

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31
Q

A drug that acts on potassium channels in pancreatic beta cells to impair insulin secretion is… A. Terbutaline B. Niacin C. Diazoxide D. Lidocaine

A

C. Diazoxide

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32
Q

Chemicals cause major cell death by all of the following mechanisms except… A. Rise in intracellular Ca++ B. ATP depletion C. Inhibition of drug metabolizing enzymes D. Overproduction of ROS

A

C. Inhibition of drug metabolizing enzymes

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33
Q

All of the following are inhibitors of cytochrome c oxidase except… A. MPP+ B. paraquat C. Azide D. Hydrogen sulfide

A

A. MPP+

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34
Q

All of the following are inhibitors of NADH coenzyme Q reductase ( complex1) except… A. Rotenone B. Paraquat C. Arsenite D. Amytal

A

C. Arsenite

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35
Q

All of the following statements are true except.. A. Macrophages can generate NO B. Macrophages can discharge myeloperoxidase into phagocytic vacuoles C. NO radical is produced by the action of NOS on arginine D. Superoxide anion and NO can combine to make peroxinitrite

A

B. Macrophages can discharge myeloperoxidase into phagocytic vacuoles

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36
Q

A contributing factor in the termination of tissue regeneration is thought to be… A. Depletion of local ATP B. Plateau of protein synthesis regulated by DNA C. Accumulation of hypochlorous acid - an antimitogen D. Dominance of TGFbeta over mitogens

A

D. Dominance of TGFbeta over mitogens

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37
Q

Overexpression of the divalent metal transporter 1 in iron deficiency will lead to increased intestinal absorption of… A. Cadmium and lead B. sodium and calcium C. Potassium and magnesium D. Lithium and aluminium

A

A. Cadmium and lead

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38
Q

An intracellular protein that increases ATP production and decreases ATP consumption is… A. ras B. BAX C. AMPK D. VEGF

A

C. AMPK

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39
Q

The heat-shock and endoplasmicreticulum stress response both… A. Repair damaged DNA B. Repair misfolded proteins C. Repair damaged lipids D. All of the above

A

B. Repair misfolded proteins

40
Q

Free radicals can be produced in inflammed tissue by the action of all of the following enzymes except… A. Aconitase B. NADPH oxidase C. Nitric oxide synthase D. Myeloperoxidase

A

A. Aconitase

41
Q

All of the following are elements of the hypoxia response except… A. Production of HIF1alpha B. Production of erythropoetin C. Production of proteins that stimulate aerobic ATP synthesis D. Production of growth factors that stimulate angiogenesis

A

C. Production of proteins that stimulate aerobic ATP synthesis

42
Q

An example of a protein that results from a mutation of an oncogene is… A. ICAM1 B. ras C. STAT D. C/EBP

A

B. ras

43
Q

All of the following are mitogenic growth factors except… A. HGF B. TGFalpha C. CTGF D. Noxa

A

D. Noxa

44
Q

If only a few mitochondria are injured in a cell, the outcome … A. Can be cell survival B. Will always be both cellular apoptosis and necrosis C. Will always be apoptosis D. Will always be necrosis

A

A. Can be cell survival

45
Q

Mechanisms opposing distribution of a toxicant to a target tissue include all of the following except… A. Plasma protein binding B. Blood-brain barrier C. Distribution to nontarget organ storage sites D. Cellular uptake transporters on target tissue

A

D. Cellular uptake transporters on target tissue

46
Q

Nonvolatile, highly lipid-soluble chemicals that are resistant to bioteansformation are eliminated from the body by all of the following processes except… A. Excretion in the bile B. Excretion in breast milk C. Exhalation D. Intestinal excretion

A

C. Exhalation

47
Q

Examples of parent xenobiotics that act as ultimate toxicants include all of the following except… A. Lead B. Carbon tetrachloride C. Tetrodotoxin D. Carbon monoxide

A

B. Carbon tetrachloride

48
Q

Examples of xenobiotics whose metabolites act as ultimate toxicants include all of the following except… A. Hexane B. TCDD C. ethylene glycol D. Acetaminophen

A

B. TCDD

49
Q

Examples of noncovalent binding of toxicants to target tissues include all of the following except… A. Binding of strychnine to glycine receptors B. Binding of hydroxyl radicals to DNA bases C. Binding of phorbol esters to protein kinase C D. Binding of warfarin to vitamin K 2,3 epoxide reductase

A

B. Binding of hydroxyl radicals to DNA bases

50
Q

The binding of hydrogen peroxide with a protein thiol group produces… A. Carbon dioxide and water B. A protein sulfenic acid C. A protein nitrosamine D. Cleavage of the peptide bond

A

B. A protein sulfenic acid

51
Q

Major target molecules for toxicants include all of the following except… A. Proteins B. Vitamins C. DNA D. Lipids

A

B. Vitamins

52
Q

All of the following toxins act by enzymatic action except… A. Ricin B. Anthrax C. Tetrodotoxin D. Botulinum

A

C. Tetrodotoxin

53
Q

Apoptotic pathways can be initiated by… A. DNA damage B. Mitochondrial insult C. Death-receptor stimulation D. All of the above

A

D. All of the above

54
Q

The enzyme that repairs oxidized protein thiols is called… A. HMG-coenzyme A reductase B. Adenyl cyclase C. Phospholipase D. None of the above

A

D. None of the above

55
Q

The mechanism of action for bleomycin-induced lung injury is presumed to be… A. DNA-adduct formation B. Generation of reactive oxygen species C. Inhibition of cytochrome oxidase D. None of the above

A

B. Generation of reactive oxygen species

56
Q

All of the following are true of oxidative DNA damage except… A. Mitochondrial DNA is much more resistant to damage than nuclear DNA B. 8-hydroxy-deoxyguanosine in the urine is a marker C. It can lead to base pair transversions D. It can lead to point mutations

A

A. Mitochondrial DNA is much more resistant to damage than nuclear DNA

57
Q

An example of a denatured protein is… A. Golgi complex B. Micronuclei C. Heinz body D. Histone

A

C. Heinz body

58
Q

An important feature of lipid peroxidation is… A. It cannot be blocked by antioxidants B. Damage propagated in a chain reaction-like manner C. It never involves the Fenton reaction D. The end products are different from the end products of the reaction of lipids with ozone

A

B. Damage propagated in a chain reaction-like manner

59
Q

Which statement is true regarding the PPAR alpha receptor A. Stimulation causes peroxisome proliferation in humans B. They are present in adipose tissue C. They involve fatty acid beta oxidation D. Thiazolidinediones act as ligands

A

C. They involve fatty acid beta oxidation

60
Q

Alterations in retinoic acid receptor (RAR) function have been associated with… A. Cardiac and vascular toxicity B. CNS and peripheral nerve toxicity C. Hepatic and renal toxicity D. Embryo and testicular toxicity

A

D. Embryo and testicular toxicity

61
Q

Proteins present in brown adipose tissue act mechanistically like… A. Pentachlorophenol B. Rotenone C. Cyanide D. Doxorubicin

A

A. Pentachlorophenol

62
Q

Which of the following regarding glutathione is false? A. It can act non-enzymatically as a radical scavenger B. It is a dipeptide C. Its levels can be upregulated in response to a need D. It is a substrate for glutathione peroxidase

A

B. It is a dipeptide

63
Q

All of the following are associated with necrosis except… A. Requirement of ATP B. Cell swelling C. Association with an inflammatory response D. Initiation by plasma membrane permeability changes

A

A. Requirement of ATP

64
Q

Another name for apoptosis is… A. Passive cell death B. Accidental cell death C. Programmed cell death D. Immune cell death

A

C. Programmed cell death

65
Q

A mitochondrial factor involved in the process of apoptosis is… A. Cytochrome a3 B. Cytochrome b6 C. Cytochrome c D. Cytochrome a1

A

C. Cytochrome c

66
Q

All of the following are true of apoptosis except… A. Cell membrane remains intact B. Early in the process, caspases are activated C. Oxidative stress can initiate it D. It can lead to carcinogenesis

A

D. It can lead to carcinogenesis

67
Q

A class of drugs that can induce apoptosis in certain cancer cells is… A. Barbiturates B. Digitalis glycosides C. Protein pump inhibitors D. COX-2 inhibitors

A

D. COX-2 inhibitors

68
Q

Which of the following signal transduction pathway/effect pairs is correct? A. ras/ERK - suppression of apoptosis B. JNK-mediated apoptosis C. p38-production of inflammatory cytokines D. All of the above

A

D. All of the above

69
Q

A drug that works by disrupting mitosis is… A. Paclitaxel B. doxorubicin C. Methotrexate D. Cyclophosphamide

A

A. Paclitaxel

70
Q

Galactosamine causes… A. Proximal tubular damage B. focal liver necrosis C. Peripheral neuropathy D. All of the above

A

B. focal liver necrosis

71
Q

Practolol was withdrawn from use because of… A. Unpredictable beta blockade B. rebound hypertension C. Teratogenicity D. Oculomucutaneous syndrome

A

D. Oculomucutaneous syndrome

72
Q

All of the following can inhibit opening of the mitochondrial permeability pore except… A. Cyclosporin A B. hydrophobic bile acids C. L-deprenyl D. Bongkrekic acid

A

B. hydrophobic bile acids

73
Q

Microcystins target… A. Adenyl cyclase B. phosphodiesterase C. Protein phosphatase D. Guanyl cyclase

A

C. Protein phosphatase

74
Q

All of the following are true of cytokines except… A. Short half-life B. act locally C. Produced in specialized organs D. Have complex interactions

A

C. Produced in specialized organs

75
Q

Molecular chaperones… A. Repair denatured proteins B. repair damaged DNA C. repair damaged tRNA D. act as catalysts for new protein synthesis

A

A. Repair denatured proteins

76
Q

Lipid repair… A. Cannot occur B. requires NADPH C. May involve catalase D. None of the above

A

A. Cannot occur

77
Q

In peripheral neurons with damaged axons, repair… A. Can occur until approx age 5 B. follows the same mechanism as CNS repair C. Requires activated neutrophils and astrocytes D. Requires macrophages and Schwann cells

A

D. Requires macrophages and Schwann cells

78
Q

Apoptosis is advantageous in… A. Neoplastic prostate cells B. female germ cells C. Cardiac myocytes D. CNS neurons

A

A. Neoplastic prostate cells

79
Q

The principle factor leading to fibrogenesis.. A. IL-8 B. TNFalpha C. TGFbeta D. IL-1

A

C. TGFbeta

80
Q

Fibrosis is harmful because… A. It may compress blood vessels B. it may contribute to tissue malnutrition C. It may interfere with mechanical organ function D. All of the above

A

D. All of the above

81
Q

All of the following are true regarding idiosyncratic drug reactions except… A. They are rare B. they are predicable from the pharmacology of the drug C. The reaction can be dose independent D. They involve genetic or acquired factors that increase susceptibility

A

B. they are predicable from the pharmacology of the drug

82
Q

All of the following would indicate initiation of a cellular stress response except… A. Downregulation of DNA repair enzymes B. induction of apoptosis C. Upregulation of antioxidant mechanisms D. Stimulation of immune response

A

A. Downregulation of DNA repair enzymes

83
Q

All of the following contribute to organ-selective toxicity except… A. Organ-selective uptake B. tissue-specific expression of transcription factors C. Number of chromosomes in nucleus D. Tissue-specific receptors

A

C. Number of chromosomes in nucleus

84
Q

The nephrotoxic effect of mercury on the kidney is thought to be mediated by… A. Blocking the effect of ADH on the collecting duct B. interfering with ionic charges on the glomerulus C. A dicysteinyl-mercury complex mimicking endogenous cysteine D. Interfering with chloride transport in the loop of Henle

A

C. A dicysteinyl-mercury complex mimicking endogenous cysteine

85
Q

An example of a soft neutorphile is… A. Sulfur in glutathione B. phosphate oxygen in nucleic acids C. Mercuric ion D. Carboxylate anion

A

B. phosphate oxygen in nucleic acids

86
Q

The Fenton reaction produces… A. Phosgene from chloroform B. formic acid from formaldehyde C. Nitrogen dioxide from ozone and nitrogen D. Hydroxyl radical and hydroxyl ions from hydrogen peroxide

A

D. Hydroxyl radical and hydroxyl ions from hydrogen peroxide

87
Q

The liver and kidney are major target organs of toxicity because… A. They both receive a higher percentage of cardiac output B. They both have substantial xenobiotic metabolizing capacity C. They both have transport systems that can concentrate xenobiotics D. All of the above

A

D. All of the above

88
Q

What are some of the drugs/chemicalas for thihc transporters play a role in absortion in the GI

A
  1. salicylate and valproate by monocarboxylate transporters
  2. some β-lactam antibiotics and ACE inhibitors by peptide transporters (PEPT)
  3. Fe2+ , Cd2+ by divalent metal transporters
  4. arsenate by phosphate transporters
89
Q

What is rate of transport dependent on ?

A
  • Conc. of chemical at absorption surface (which in turn is dependent on rate of exposure)
  • area of the exposed site
  • characteristics of the epithelial layer (eg: thickness of the stratum corneum) etc.

LIPID SOLUBILITY is the MOST IMPORTANT property

90
Q

What are examples of chemicals that undergo presystemic elimination

A
  • ethanol: By Alcohol dehydrogenase in gastric mucosa cells
  • Cyclosporine: moved from enterocyte into lumen by MDR1 (also hydroxylated by CYTP3A4 in these cells
  • Morphine: glucuronidated in intestinal mucosa and liver
91
Q

What is the downside of presystemic elimination?

A

may contribute to toxicity to organs involved such as GI, liver, lungs etc. (eg: ethanol, iron salts, α-amanitin, paraquat)

92
Q

whats are the mecahnisms facilitating transport/distribution of toxicants towards the target?

A

(1) the porosity of the capillary endothelium
(2) specialized membrane transport

(3) accumulation in cell organelles,
(4) reversible intracellular binding

93
Q

what are some of the transporters facilitating transport of toxicants into the cell?

A
  • Arsenite via aquaglyceroporin channels
  • Cations such as Pb abd Ba via voltage gated Ca channels
  • Thallium (thallous ion) via Na K ATPase
  • Li via Na channels into excitable cells and renal duct
  • Praquat enters pneumocytes via unknow transporters
  • MPTP (a neurotoxin that destroys dopaminergic receptots in brain and causes Parkinsons like disease via its toxic metabolite MPP+) is taken in via dopamine receptor
  • Small MW cmpds. like metformin, cimetidine, cisplatin via Organic cation transporters (OCT)- from blood into liver thru OCT1
  • from blood into renal proximal tubular cells thru OCT2
  • Hepatic uptake and toxicity of microcrystin (from blue green algae) via OATP
  • Renal tubular uptake of ochratoxin and mercuric ion
94
Q

Liver and Kidney efficiently remove mostly highly
hydrophilic, usually ionized chemicals such as organic acids and bases

A
95
Q

Why can liver and kidney mostly remove only hydrophilic substances?

A

(1) in the renal glomeruli, only compounds in plasma water can be filtered
2) Transporters are specialized mainly for hydrophilic substances
3) only hydrophilic chemicals are freely soluble in the aqueous urine and bile

96
Q

Elimination of NONVOLATILE, HDROPHOBIC substances is very inefficient. What are the inefficneet ways by which they can be excreted?

A

1) Excreted into milk by mammary glands

2)excretion in bile in association
with biliary micelles and/or phospholipid vesicles

3)intestinal excretion

97
Q

What does extent of reabsorption ( from renal tubules back to bed of capillaries) by diffusion depend on for

a) HYDROPHOBIC and
b) HYDROPHILIC substances?

A
  • For HYDROPHOBIC subtances- extent of lipid solubility
  • For HYDROPHILIC substances- extent of ionization ( as in case of organic acids and bases) ; therefore strongly pH depedent
  • Some reabsorbed via t_ransport proteins_
    • (eg: PEPT can move peptidomimetic drugs, likesome β-lactam antibiotics and ACE inhibitors)
    • Anion transporters (eg: sulfate and phosphate transporters move toxic metal anions)

TOX-CD (8 decks)

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