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Mechanisms Flashcards

1
Q

Tetrodotoxin

Saxitoxin

A

Parent toxicant is ultimate toxicant

Blocks voltage gated Na+ channels in neurons resulting in inhibition of motor neurons and paralysis

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2
Q

2,4-dinitrophenol (precursor for disinfectant,pesticides)

A

Enters the mitochondrial matrix and its presence destroys the proton gradient leading to mitochondrial dysfunction->hyperthermia, seizures

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3
Q

Most important property affecting absorption

A

Lipid solubility

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4
Q

What is the ultimate toxicant of amygdalin and what is it?

A

HCN

Found in seeds of apricots, apples, peaches and plums

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5
Q

What is the ultimate toxicant of arsenate?

A

Arsenite

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6
Q

What is the ultimate toxicant of fluoroacetate and what is it?

A

Fluorocitrate- inhibits aconitase (part of TCA cycle)

Pesticide

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7
Q

What is the ultimate toxicant of ethylene glycol?

A

Oxalic acid

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8
Q

What is the ultimate toxicant of hexane and what is it?

A

2,5-hexanedione- neurotoxic

Part of gasoline, solvents

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9
Q

What is the ultimate toxicant of acetaminophen?

A

N-acetyl-p-benzoquinoneimine (NAPBQI)

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10
Q

What is the ultimate toxicant of carbon tetrachloride (CCl4)?

A

CCl3OO. (trichloromethyl peroxy radical) which is hepatotoxic

Refrigerant, fire extinguisher, solvent

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11
Q

What is the ultimate toxicant of benzo[a]pyrene (BP) and what is it?

A

BP-7,8-diol-9,10-epoxide
BP-radical cation

Carcinogen found in coal tar, tobacco smoke and charred meat

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12
Q

What is the ultimate toxicant of hydrogen peroxide?

A

Hydroxyl radical (HO . )

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13
Q

What is the ultimate toxicant of diquat and what is it?

A

Hydroxyl radical

Herbicide

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14
Q

What is the ultimate toxicant of doxorubicin?

A

Hydroxyl radical

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15
Q

What is the ultimate toxicant of nitrofurantoin and what is it?

A

Hydroxyl radical

Antibiotic that concentrates in urine, damages bacterial DNA

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16
Q

What is the ultimate toxicant of Cr(V), Fe(II), Mn(II), and Ni(II)?

A

Hydroxyl radical

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17
Q

What is the ultimate toxicant of paraquat and what is it?

A

Peroxynitrite (ONOO-)

Herbicide

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18
Q

Mechanisms that facilitate distribution of a toxicant to a target:

A
  1. Porosity of capillary endothelium (hepatic sinusoids and renal peritubular capillaries)
  2. Specialized membrane transport
  3. Accumulation in cell organelles
  4. Reversible intracellular binding
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19
Q

Mechanisms that oppose distribution of a toxicant to a target:

A
  1. Binding to plasma proteins
  2. Specialized barriers (BBB)
  3. Distribution to storage sites (adipose)
  4. Association with intracellular binding proteins
  5. Export from cells (MDR1)
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20
Q

What type of chemicals lack efficient elimination methods and what are these methods?

A

Nonvolatile, highly lipophilic (eg: polyhalogenated biphenyls, chlorinated hydrocarbon insecticides)

  1. Excretion dissolved in milk lipids
  2. Excretion in bile micelles or phospholipid vesicles in bile
  3. Intestinal excretion
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21
Q

What is the ultimate toxicant of parathion and what is it

A

Paraoxon (cholinesterase inhibitor)

Organophosphate insecticide

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22
Q

What is the ultimate toxicant of cephoperazone (cephalosporin)?

A

MTT (1-methyl-tetrazole-5-thiol)

inhibits vitamin K epoxide reductase

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23
Q

Toxication (metabolic activation, biotransformation to harmful products) often forms reactive substances. Name these 4 reactive substances and how they are formed.

A
  1. Electrophiles- electron deficient and react with nucleophiles, often produced by insertion of an oxygen or heterolytic bond cleavage, often catalyzed by P450s
  2. Free radicals- unpaired electron/s in outer orbital, formed by accepting or losing an electron or by homolytic covalent bond fission
  3. Nucleophiles- uncommon, eg: amygdalin to HCN
  4. Redox-active reactants-
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24
Q

Fenton reaction

A

Hydrogen peroxide (HOOH) reacts with transition metal ions (Fe(II), Cu(I), Mn(II), Cr(V), Ni(II)) and undergoes homolytic cleavage to hydroxyl OH- and hydroxyl free radical HO .

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25
Q

What is the ultimate toxicant of dapsone and what is it?

A

Dapsone hydroxylamine (an N-hydroxyl arylamine) which produces methemoglobin

Dapsone (diaminodiphenyl sulfone) is an antibiotic used to treat leprosy; inhibits bacterial synthesis of dihydrofolic acid by competition with para-aminobenzoate for the active site of dyhydropterate synthase; also is anti-inflammatory by inhibiting (reversibly binding) myeloperoxidase

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26
Q

What is the ultimate toxicant of primaquine and what is it?

A

5-hydroxyprimaquine- cooxidized with oxyhemoglobin forming methemoglobin and HOOH

Used to treat malaria and pneumocystis

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27
Q

Detoxication of chemicals without functional groups

A

Eg: benzene, toluene

  1. Functional group added (hydroxyl, carboxyl) by CYP450
  2. Endogenous acid added by a transferase
  3. Resulting hydrophilic organic acids are readily excreted
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28
Q

What is the ultimate toxicant of NNK and what is it?

A

NNAL (
Potent carcinogen
Nicotine derived nitrosamine ketone

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29
Q

Detoxication of nucleophiles

A
  1. Conjugation at the nucleophile group
    Hydroxylated ones are conjugated by sulfation, glucuronidation, or mathylation
    Thiols are methylated or glucuronidated
    Amines and hydrazine are acetylated
  2. Prevents conversion to free radicals

Alternatively- oxidation by flavin containing monooxygenases, oxidation to carboxylic acids

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30
Q

Detoxication of cyanide

A

Rhodanese or mercaptopyruvate sulfurtransferase converts cyanide to thiocyanate

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31
Q

Detoxication of electrophiles

A

Conjugation with glutathione (thiol nucleophile)
Can occur spontaneously or by glutathione-S-transferases
-Metal ions are readily detoxicated by glutathione

Covalent binding to proteins can be detoxication if protein isn’t critical or antigenic

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32
Q

Detoxication of free radicals

A

Superoxide dismutase in the cytosol and mitochondria convert O2-. to HOOH which is reduced to water by

  1. catalase in the peroxisomes (and cardiac mitochondria)
  2. Selenocysteine containing glutathione peroxidases in the cytosol and mito
  3. Peroxiredoxins in the cytosol, mito and ER (can be overwhelmed)

No detox mechanism for hydroxyl radical

ONOO- selenocysteine GPs, peroxiredoxins, selenoprotein P, reactions with oxyhemoglobin, heme peroxidases, albumin

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33
Q

Detoxication of protein toxins

A

Intracellular proteases
Eg:
Venom toxins (bungarotoxin, erabutoxin, phospholipase) have disulfide bonds and are inactivated by thioredoxin

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34
Q

Where does 2-napthylamine come from and what are the effects?

A

Azo dye, tobacco smoke, carcinogen

Detoxicated in liver, but deconjugation and protonation in bladder leads to arylnitrenium ion -Causes bladder cancer

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35
Q

Ways in which detoxication fails

A
  1. Overwhelmed processes
  2. Toxicant inactivates detoxicating enzyme
  3. Reversal of conjugation reactions
  4. Detoxication can form harmful byproducts
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36
Q

Vinyl chloride

A

Vinyl chloride epoxide

Genotoxic

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37
Q

Types of reactions with toxicants

A
  1. Noncovalent binding- usually reversible; involves membrane receptors, intracellular receptors, ion channels, some enzymes, intercalation of DNA
  2. Covalent binding- irreversible; electrophilic toxicants form adducts with nucleophilic macromolecules such as proteins and nucleic acids; hard electrophiles react with hard nucleophiles, same for soft.
  3. Hydrogen abstraction- neutral free radicals can steal a H from endogenous molecules, can then form cross links with DNA and others
  4. Electron transfer- oxidation of Fe(II) in hemoglobin to Fe(III) methemoglobin
  5. Enzymatic reactions- can hydrolyze critical proteins
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38
Q

Ricin

A

N-glycosidase plant toxin - hydrolyzes a glycosidic bond in ribosomal RNA blocking protein synthesis

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39
Q

Botulinum toxin

A

Zn protease- hydrolyzes the fusion proteins that assist in exocytosis of ACh in neurons, esp motor neurons-> paralysis

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40
Q

Lethal factor (anthrax)

A

Zn protease- inactivates MAPKK-> cell death

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41
Q

Protein phosphatase 2A (PP2A)

A

Soluble Ser/Thr phosphatase in cells that antagonizes MAPK, also removes phosphate from p34^cdc2 (mitosis triggering kinase)

Inhibited by microcystin-LR in blue green algae and okadaic acid in dinoflagellates (chronic low levels lead to carcinogenesis)

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42
Q

What is the MOA of Veratrum californicum?

A

Cyclopamine -> Inhibits Smoothened -> Disruption of Hh- Gli signaling ->teratogenic

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43
Q

Three mechanisms toxicants can inflict cell death

A
  1. ATP depletion
  2. Sustained rise in intracellular Ca++
  3. Overproduction of ROS and RNS
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44
Q

What are the different chemical classes that interfere with mitochondrial ATP synthesis?

A
  1. Class A- interfere with delivery of hydrogen (in NADH) to the electron transport chain
    eg: fluoroacetate inhibits the citric acid cycle and therefore the formation of the reduced cofactors
  2. Class B- inhibit transfer of electrons along the chain to oxygen
    eg: rotenone, cyanide
  3. Class C- interfere with oxygen delivery to cytochrome oxidase, the terminal electron transporter
    eg: all chemicals that cause hypoxia ultimately act here
  4. Class D- inhibit ATP synthase, can occur
    a. Directly
    b. Interference with ADP delivery
    c. Interference with inorganic phosphate delivery
    d. Deprivation from ATP synthase’s driving force (influx of proteins into the matrix
  5. Class E- cause mito DNA injury impairing synthesis of proteins
    eg: zidovudine (and other dideoxynucleoside AIDS antivirals)
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45
Q

Protonophoric uncouplers

A

eg: 2,4-dinitrophenol, pentachlorophenol

Import protons into the mito matrix, dissipating the proton gradient

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46
Q

Why is sustained elevated intracellular Ca++ harmful?

A
  1. Deplete energy reserves
  2. Dysfunction of microfilaments -> plasma membrane blebbing
  3. Activates hydrolytic enzymes
  4. Generates ROS and RNS
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47
Q

How does increased intracellular calcium deplete energy?

A
  1. Uptake by mito uniporter dissipates the mito membrane potential
  2. Can cause oxidative damage to the inner mito membrane
  3. ATP consumption by Ca++
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48
Q

How does increased intracellular calcium causing blebbing?

A

Dissociation of actin filaments from alpha-actinin and fodrin-> actin no longer anchored to plasma membrane-> blebbing-> predisposed to rupture

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49
Q

What are calpains?

A

Calcium activated neutral proteases-

  1. Hydrolyze actin binding proteins
  2. activate phospholipases
  3. activate Ca++Mg++ dependent endonuclease->fragmented chromatin
  4. Lock topoisomerase II in a form that cleaves but does not religate DNA
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50
Q

Intracellular calcium activates enzymes that generate ROS/RNS in what ways?

A
  1. Activation of dehydrogenases in the TCA cycle accelerates hydrogen output increasing electron transport, but ATP synthase activity is decreased so more superoxide radicals
  2. Activates proteases that convert xanthine dehydrogenase into xanthine oxidase whose byproducts are superoxide radial and HOOH
  3. Activates NOS in neurons and endothelial cells leads to peroxynitrite (can increase its own formation by inhibiting Mn-SOD)
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51
Q

What results from release of cyt c?

A
  1. It is the penultimate link in electron transport, so decreased ATP synthesis and increased superoxide radical
  2. Along with ATP/dATP activates Apaf-1->oligomerize and bind procaspase-9-> caspase-9 activation
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52
Q

What are caspases?

A

Cysteine proteases that cleave proteins at aspartate residues
Initiators- 8 & 9
Effectors- 3, 6, & 7
Smac/Diablo and Omi/HtrA2 capture caspases to inactivate them

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53
Q

Autophage proteins

A
  1. Pink1- protein kinase on the MOM that accumulates there after dissipation of the MMP
  2. Parkin- cytosolic, recruited by Pink1, polyubiquitintaes itself and others in number 3
  3. MOM protein mitofuscins (Mfn) and voltage dependent anion channel
  4. p62 binds ubiquitinated proteins and LC3
  5. LC3- cytosolic protein that is cleaved and conjgates with phosphatidylethanolamine
    6.
54
Q

Trefoil factors (TFFs)

A

Protease resistant proteins secreted by specific mucosal cells and associated with mucous layer of GI tract
Rapidly increased in response to mucosal damage-> potent motogens that stimulate epithelial migration to cover defect

55
Q

Upon hepatic injury, what mediator cause proliferation of stellate cells?

A

PDGF
which activates the PI3K-Akt pathway->proliferation and inactivation of the transcription factor FOXO1 (normally increases p27 which halts cell cycle at G1)

56
Q

Upon hepatic injury, what mediator acts on stellate cells to induce transdifferentiation and production of ECM (collagen, fibronectin, tenascin, proteoglycans)?

A

TGF-b

Activates Ser/Thr kinase receptor->phosphrylation of Smad2 and 3

57
Q

NOX

What cells and what does it do?

A

NADPH oxidase
macrophages and granulocytes
Rapid electron transfer from NADPH to oxygen, forming superoxide radical

58
Q

NOS

what cells and what does it do?

A

Nitric oxide synthase
Macrophages
Converts L-arginine and oxygen to L-citrullin and nitric oxide radical
Nitric oxide radical can react with superoxide radical and carbon dioxide to form nitrogen dioxide radical and carbonate anion radical

59
Q

Myeloperoxidase is important in which cells and what does it do?

A

Granulocytes
Catalyzes formation of hypochlorous acid (HOCl) which is a strong oxidizing agent and can combine with superoxide radical to form hydroxide radical

60
Q
  1. What are the 3 major proinflammatory cytokines that induce fever, anorexia, etc?
  2. What cytokine is important in vial infections?
A
  1. IL-1
    IL-6
    TNF-alpha
  2. IFN-gamma
61
Q

Which cytokines act as positive or negative growth factors?

A

IL-2,3,4,7,10,11,12, GM-CSF

62
Q

Which cytokine is the major mediator of hepatocyte secretions of APPs and what cytokine suppresses it?

A

IL-6

IL-10 suppresses it (both are released by Kuppfer cells)

63
Q

What are the 4 key steps in risk assessment?

A
  1. Hazard identification- does it cause adverse health effects?
  2. Does-response assessment- what is the relationship between dose and response?
  3. Exposure assessment- what types/levels/duration of exposure are expected?
  4. Risk characterization- what is the incidence of exposure, how robust is the evidence, and is there a mode of action?
64
Q

Standard cancer bioassay features:

A

2 species, both sexes
50 animals per dose group
Near lifetime exposure
Typical dose levels based on MTD: 90%, 50%, 10-25%

65
Q 
Reference dose (RfD) or
Allowable daily intake (ADI)

Calculation

A

UF x MF

uncertainty factors- to account for interspecies differences(10-fold), intraspecies differences (10-fold), experimental inadequacy, if only LOAEL is known (10-fold)

modifying factor

66
Q

Margin of exposure (MOE) calculation

A

Daily intake in mg/kg

High MOE=safe

67
Q

What is the Benchmark dose (BMD) approach?

A

The dose response curve is modeled and is used to determine and the predicted dose at a specified response level (1%,5%,or 10%)
Can also use a 95% lower confidence boundary (BMDL)

The BMD can be used in place of NOAEL in the RfD calculation

68
Q

Advantages of BMD approach:

A
  1. Can take the dose response curve into account
  2. Inclusion of a confidence limit
  3. Use of a consistent response rate to calculate RfD across studies
69
Q

From most effective to least effective, list the routes of exposure:

A

IV, inhalation, IP, subQ, IM, ID, oral, dermal

70
Q

Define acute, subacute, subchronic, chronic

A

Acute- exposure less than 24 hrs (inhalation usually for 4 hours)
Subacute- repeated exposures for 1 month or less
Subchronic- repeated exposure fro 1-3 months
Chronic- usually 1 year or longer

71
Q

What are the 2 types of dose response relationships?

A
  1. Individual or graded response, measured effect is continuous over a range of doses
  2. Population or quantal response that characterizes the distribution of a response in a population
72
Q

What are probit units?

A

NED+5= probit

NED is the normal equivalent deviations, converts sigmoid curve of a quantal dose response curve to a linear form.

73
Q

What toxins have a U-shaped dose response curve?

A
  1. Vitamins and essential nutrients

2. Agents that are beneficial at low doses, but toxic at higher doses. ( the “response” on the y-axis varies with dose)

74
Q

What is a nonmonotonic dose response curve?

A

Curve for Chemicals that exert their effects via modification of hormonal responses
Eg: endocrine disrupters
Mechanisms:
1. Upregulation of receptors at low conc and down regulation at high conc
2. Integration of multiple monotonic dose response curves with some common endpoints but opposite effects

75
Q

Therapeutic index (TI) calculation

A

ED50

Higher means safer

76
Q

Margin of Safety (MOS) calculation

A

ED99

Higher means safer

77
Q

Chronicity index

A

90 dose TD50 (mg/kg/day)

1= no cumulative effect
90= absolute cumulative effect
78
Q

What is the uneconomic form in selective toxicity?

A

The injured organisms or tissue

The economic form is protected

79
Q

MTD definition

A

Various definitions, but sometimes :

The dose that suppresses body weight gain slightly (10%) in a 90 day subchronic study

80
Q

Developmental/repro tox segment 1 tests:

A

Rats only
Male rats given compound for 60 days prior to breeding, females 14 days, continues throughout gestation and lactation
Measure:
Percent females pregnant, number of live and stillborn offspring, weight, growth and survival of offspring for 3 weeks

81
Q

Developmental/repro tox segment 2 tests:

A

2 species (rodent and nonrodent)
Dosed 1-3 times during organogenesis (rodent day 7-17, rabbit day 7-19), fetuses removed on delivery day
Measure:
Uterus weight, number of live, dead, resorbed fetuses, live fetus weights and examined for skeletal and soft tissue anomalies

82
Q

Developmental/repro tox segment 3 tests:

A

Administer to rats from day 15 of gestation to delivery and lactation for 3 weeks
Measure:
Birth weight, survival and growth for 3 weeks

(multigenerational study may take the place of segment 3 tests)

83
Q

Fertility index

A

Percentage of mating resulting in pregnancy

84
Q

Gestation index

A

Percentage of pregnancy resulting in live litter

85
Q

Viability index

A

Percentage of offspring that live 4 days or longer

86
Q

Lactation index

A

Percentage of animals alive at day 4 that make it to day 21

87
Q

ICH guidelines on the 6 stages of development

A 
Stage A- premating and conception
B- conception to implantation
C- implantation to closure of hard palate
D- closure of hard palate to birth
E- birth and weaning
F- weaning to sexual maturity
88
Q

For carcinogenicity studies with no known MTD, what calculation can be used to determine the dose?

A

Daily dose 25 times the AUC of humans given the highest single daily dose

89
Q

Which rat strain has mammary tumors responsive to estrogen?

A

Sprague-Dawley

90
Q

What is the MVK model?

A

Model used in risk extrapolation-BBDR (biologically based dose response) model
Based on 2-stage (mutation) model of carcinogenesis

91
Q

Lifetime average daily dose (LADD) calculation

A

bodyweight x lifetime

92
Q

Incremental lifetime cancer risk (ILCR) calculation

A

LADD x bioavailability x q

q is the slope factor

93
Q

What is the food quality protection act (FQPA) of 1996?

A

mandated a health-based standard for pesticides used in foods that takes into account cumulative exposure from all sources, provided special protections for babies and infants, streamlined the approval of safe pesticides, established incentives for the creation of safer pesticides, and required that pesticide registrations remain current

94
Q

Name the parent to toxicant, the enzyme catalyzing the reaction and the toxic effect.
Acetaldehyde

A

Ethanol
Alcohol dehydrogenase
Hepatic fibrosis

95
Q

Name the parent to toxicant, the enzyme catalyzing the reaction and the toxic effect.
2,5-hexanedione

A

Hexane
CYP
Axonopathy

96
Q

Name the parent to toxicant, the enzyme catalyzing the reaction and the toxic effect.
Acrolein (3 different parent toxicants)

A

Allyl alcohol. Allyl amine. Cyclophosphamide.
ADH. MAO. CYP->spontaneous cleavage.
Hep necrosis. Vascular injury. Hemorrhagic cystitis.

97
Q

Name the parent to toxicant, the enzyme catalyzing the reaction and the toxic effect.
Atropaldehyde (2-phenylacrolein)

A

Felbamate (anticonvulsant that potentiates GABAa receptors and blocks NMDA receptors; also it inhibits CYP2C19)
Esterase -> ADH -> spontaneous cleavage
BM and liver injury

98
Q

Name the parent to toxicant, the enzyme catalyzing the reaction and the toxic effect.
Diaquo-diamino platinate (II) ion

A

Cisplatin
Spontaneous rearrangement
Renal tubular necrosis

99
Q

List common electrophiles from soft to hard

A

quinones, unsaturated ketones, silver, mercury
epoxides, lactones, aryl halides
aryl carbonium ions, chromium, zinc, lead
benzylic carbonium ions, nitrenium ions
alkyl carbonium ions, lithium, calcium, barium

100
Q

List common nucleophiles from soft to hard

A 
Thiol sulfurs
Methionine sulfurs
Protein amino group nitrogens
Purine base nitrogens
Purine and pyrimidine oxygens
Phosphate oxygen in nucleic acids
101
Q

List 3 toxicants that activate the AhR

A

TCDD
Polychlorinated biphenyls
Polycyclic aromatic hydrocarbons

102
Q

List toxicants/drugs that activate the pregnane X receptor

A 
pregnenolone 16a-carbonitrile (PCN)
dexamethasone
spironolactone
cyproterone
rifampicin
zearalenone
litocholic acid
103
Q

Two important families of xenobiotic transporters and their subfamilies

A
  1. ATP binding cassette (ABC)- includes MDR-1, MRPs, BCRP

2. Solute carriers (SLC)- includes OATP, OAT, OCT, OCTN, PEPT, MATE

104
Q

What is PhIP (2-amino-1-methyl-6-phenylinidazo pyridine

A

Carcinogen produced during meat cooking

MRP2 in the small int limits absorption

105
Q

How are most GI toxicants absorbed?

A

Simple diffusion

106
Q

What is pralidoxine chloride?

A

Regenerates acetylcholinesterase that has been bound by OP insecticides

107
Q

What is the predominant absorption pathway for nanoparticles in the GI tract?

108
Q

What is the effect of grapefruit juice on GI absorption?

A

Naringin inhibits the function of transporters such as MDR1 reducing drug efflux and increasing absorption, OR such as OATP1A2 reducing drug absorption

109
Q

GI drug absorption is often higher in what species and why?

A

Dog

Increased paracellular absorption

110
Q

List the agents that cause renal damage and tumors in male rat kidneys but not other sex/species and why does this occur?

A

D-limonene (orange juice)
2,4,4-trimethylpentane (gasoline)

Alpha2-microglobulin is only present in male rats and binds these compounds causing them to be taken up by proximal tubules

111
Q

Why does chloroquine have such a high volume of distribution?

A

It is a cationic amphiphile that is non-ionized at physiologic pH, but once in cells, is taken up by lysosome where it becomes ionized and trapped. This leads to lysosome dysfunction and phospholipidosis

112
Q

List compounds that accumulate in fat

A

Pesticides: aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, mirex, toxaphene
Polychlorinated and polybrominated biphenyls
Dioxins
Furans

113
Q

List 3 compounds that incorporate into the bone matrix

A

Fluoride (substitutes for OH-)
Lead (subs for Ca)
Strontium (subs for Ca)

114
Q

How does methyl mercury enter tissues, including the brain?

A

Combines with a cysteine forming a complex similar to methionine-> uses large amino acid carrier for uptake

115
Q

For highly soluble gases (high blood-gas partition coefficient), what is the factor limiting the rate of absorption?

A

Respiratory rate

116
Q

For gases with a low partition coefficient, what is the factor limiting the rate of absorption?

A

Blood flow

117
Q

Which gases take longer to reach equilibrium with the blood? (high or low solubility)

A

high solubility

118
Q

What are the characteristics that affect site of deposition of aerosolized particles and how are they cleared?

A

Site of deposition- Particle size

  1. 5um or larger deposit in nasopharynx- swallowed or absorbed through epithelium
  2. 2.5 um deposit in tracheobronchiolar area - mucociliary clearance
  3. 1 um or smaller- penetrate alveolar sacs; clearance is inefficient: scavenged by alveolar macs, aspirated into the mucociliary apparatus, or absorbed into lymphatics or blood
119
Q

What factors affect urinary excretion of organic acids and bases?

A 
Urine pH (excretion of ionized moiety is favored) 
urine flow rate (tubular diffusion)
120
Q

Why organ does cadmium target and why?

A

Cadmium is bound to metallothionein in the blood and is reabsorbed by kidney tubules after filtration->nephrotoxicity

121
Q

What are the 3 classes of compounds excreted in bile and give examples of each

A

Class A - equal conc in bile and plasma: Na, K, glucose, Hg, Thallium, Cesium, Co
Class B- more conc in bile: bile acids, bilirubin, Pb, As, Mn, xenobiotics
Class C- less conc in bile: inulin, albumin, Zn, Fe, Au, chromium

122
Q

What is indocyanine green used for? (ICG)

A

Diagnostic to evaluate liver function
Injected IV and plasma levels measured, decreased clearance indicates reduced hepatic blood flow or more likely hepatic function

123
Q

What 4 characteristics are used to predict poor drug absorption (rule of 5)?

A
  1. Molecular weight greater than 500
  2. C log P greater than 5 (measure of lipophilicity based on partition coefficient; higher logP is lipophilic)
  3. More than 5 H-bond donors
  4. More than 10 H-bone accepters
124
Q

Chemicals that produce dispositional tolerance:

A

Carbon tetrachloride and cadmium

Phenobarbital to itself

125
Q

Name the 4 categories of enzyme systems that biotransform xenobiotics based on the rxn they catalyze and example of each

A 
Phase I
1. Hydrolysis- carboxyesterase
2. Reduction- carbonyl reductase
3. Oxidation- CYP
Phase II
4. Conjugation- UDP-glucuronyltransferase
126
Q

Where does indol-3-carbinol come from and what happens when exposed to gastric acid?

A

Breakdown of cruciferous veggies

Gastric acid catalyzes conversion to a dimer which is potent agonist of AhR -> induction of enzymes including CYP

127
Q

Which two enzymes in humans metabolize over half of all oral drugs in use?

A

CYP2D6

CYP3A4

128
Q

Drug conjugates are actively transported into bile primarily by what transporter?

Same question for transport into blood from liver?

A

MRP2 (ABCC2)

129
Q

What are the major xenosensors that upregulate biotransforming enzymes?

A

AhR- CYP1 enzymes
CAR- CYP2B, 2C, 3A
PXR- CYP2B, 2C, 3A
PPARa- CYP4

130
Q

What suppresses drug metabolizing enzymes and how?

A

Inflammation, cancer, vaccination, etc. activate NF-kB which suppresses the xenoreceptors and decreases CYP expression

131
Q

How does rifampin cause osteomalacia?

A

Rifampin activates PXR which increase CYP3A4 -> conversion of Vit D to inactive metabolite

Toxicology (2 decks)

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