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Toxicology > Chapter 2 (exam 1) > Flashcards

Chapter 2 (exam 1) Flashcards

1
Q

Absorption factors

A

Variables in Fick’s rate of diffusion

  • polarity, ionization (Kow)
  • surface area
  • # and thickness of membranes
  • Conc gradient (high - low)
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2
Q

DMSO

A

Dimethyl sulfoxide

  • Moves across skin barrier rapidly
  • Dissolve toxicant in DMSO for rapid dermal uptake
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3
Q

Partition Coefficient

A

measures polarity

  • Kow = conc in the organic layer/conc in the water layer
  • high Kow is highly nonpolar and crosses lipid membranes readily
  • determine polarity based on structure
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4
Q

Ionization

A

Neutral compounds diffuse across membranes better than charged ions
-dependent on the pH of the environment

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5
Q

pKa and environment pH example

A

Aspirin pKa of -COOH = 3.49, stomach pH =2, GI pH =6
-uptake greater in stomach because at a lower pH HA will be dominant over A- and the more neutral compound will diffuse better over the nonpolar lipid membrane

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6
Q

Why do pharmaceuticals come with HCL

A
  • Forms a salt, which is easier to transport and package

- The toxin has little effect on the pH of the environment

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7
Q

Concentration Gradient

A
  • more probably that high conc molecules will hit the membrane and cross over
  • based on random motion
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8
Q

Passive diffusion

A

gradient dependent

  • probability of hitting the membrane
  • conc in blood is very close to zero, fast motion removes the substance quickly
  • “hitchhiker” uptake from Pb2+ looking like Ca2+
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9
Q

Active Transport

A
  • burns ATP
  • couple with nonspontaneous
  • against the gradient
  • use transport proteins and enzymes as carriers
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10
Q

Filtration

A

passive diffusion of polar/charged substance through small pores

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11
Q

Endocytosis/pinocytosis

A

particles into the cells by forming vesicle from membrane

-nanoparticles

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12
Q

GIT

A 
epithelial cells
continuous with exterior
high surface area
pH - stomach(2) intestine(6) blood(7.4)
mostly passive diffusion
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13
Q

Lungs

A
  • thin membrane
  • facilitate exchange
  • difference between upper and lower
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14
Q

Particle Size in Lungs

A

Large are filtered out by the URT

Small penetrate to the LRT

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15
Q

Gases and Aerosols in Lungs

A
  • some particulate filtered out by URT
  • permanent gases make it to the LRT
  • PM2.5 - particle smaller than 2.5 um gets to LRT, less than 1 um gets to alveoli
  • water soluble gases dissolve into nasal fluid
  • low water solubility go to LRT
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16
Q

Reactivity in Lungs

A
  • highly reactive effect the URT
  • low reactivity effect the LRT
  • Ozone - 30% into URT even though low water solubility. High reactivity
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17
Q

Brick and Mortar model of skin

A

Keratinocytes/corneocytes are polar
surrounded by nonpolar lipids
-Tortuosity describes the indirect pathway
-no active transport because cells are dead

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18
Q

Solvents through dermis

A

nonpolar increase fluidity of the lipids or remove it. Less barrier to move through

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19
Q

Perfusion

A

blood flow to an organ or tissue. More exposure to toxicant in the higher perfused tissue
high- brain, liver , kidneys
low- bone, adipose,

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20
Q

Depots

A

accumulation of a chemical in a specific tissue based on physical or chemical properties

  • nonpolar compounds in fat
  • Sr2+ and Pb2+ on bone
  • albumin
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21
Q

Albumin

A
  • blood plasma protein
  • attracts nonpolar and ionic compounds to minimize the surface area exposed to water
  • common for antibiotics
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22
Q

Deports (reversibly bound)

A

Follow LeChatelier’s principle

  • when blood conc decreases, more is released
  • lead in kids, removing them from the lead environment will cause it to be released from depots
  • does not apply to irreversible binding
  • graphs
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23
Q

Distribution barrier

A

Blood brain barrier
-blood vessels have smaller/fewer pores, more specific transporters, tighter junctions between cells
Blood placenta barrier
-not as selective as blood brain barrier

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24
Q

Metabolism Goal

A
  • facilitate excretion

- increase aqueous solubility

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25
Q

Nonpolar risks

A
  • increased uptake
  • increased storage in depots and accumulation
  • orange baby noses from accumulation of beta-keratine in carrots and sweet potatoes
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26
Q

Pro/Con to modifying chemical structure

A

pro-detoxification
-decrease receptor compatability
con - metabolite more toxic than parent compound
- highly reactive metabolite

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27
Q

Membrane thickness

A

GIT - 30um
Respiratory - 0.4 - 1.5 um
Skin - 100-200 um
injection - 0 um

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28
Q

Phase II metabolism (general)

A

increase solubility by adding small polar molecule (conjugation reaction)

  • sugar, polypeptides add -OH groups and some proteins can be ionized
  • often occurs at the site of phase I functional group
  • reliably detoxifies
  • creates large polar region to increase excretion
  • relies on enzyme
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29
Q

Phase I metabolism (general)

A

generally oxidation that increases aq solubility by adding a polar functional group

  • OH, -COOH (ionizable), R=O
  • single functional group
  • more reactive than phase II
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30
Q

Phase I enzymes

A

-cytochrome P450s
Flavin containing monooxygenases (FMO)
-Dehydrogenases

31
Q

P450 general

A
  • enzymes for phase I
  • 2000+ vary by substrate specificity and organism
  • found in portals of entry (skin, nasal mucosa, lungs, GIT, liver, kidney)
  • metabolize xenobiotics and endogenous materials
32
Q

P450 as microsomal enzyme

A
  • “small bodies” organelles in a cell
  • Primarily in smooth endoplasmic reticulum
  • isolate by lysing cell and centrifuge
  • -s9 fraction is the percentage of microsomes and cytosolic enzymes
33
Q

P450 general reaction

A

RH + O2 + NADPH + H+ = ROH + H2O + NADP+

-NADPH to help the O2 oxidize C-H bond

34
Q

P450 catalytic cycle

A 
RH present at all times
-Fe3+ from heme and NADPH e- = Fe2+
-Fe2+ and O2 = Fe3+O2-
-NADPH e- = Fe3+[O2]2-
- 2H+ leave as water = [Fe-O]3+
-Fe3+ + ROH
(can all occur in vitro)
35
Q

P450 example

A

benzo(a)pyrene is a polycyclic carbon

  • product of incomplete combustion and cig smoke
  • P450 produces an epoxide
  • epoxide hydrolase produces diol
  • P450 and diol make diol epoxide(toxic) that is not a substrate of P450
36
Q

O-dealkylation

A
  • P450 reaction
  • chlorfenvinfos - organophosphate pesticide
  • remove alkyl group and leave -OH
  • as EN atoms, ONSP
37
Q

Flavin-containing Monooxygenases (FMO)

A
  • microsomal enzyme for phase I
  • NADPH and O2 required
  • goes between quinone(oxidized =O) and hydroquinone(reduced -OH)
  • less reactive than P450
38
Q

Alcohol dehydrogenase (ADH)

A

-in cytosol, of liver, kidney, lungs
-effective on primary and secondary(slower) alcohols
-Produces aldehydes and ketones, which are more toxic (activation)
RCH2OH + NAD+ = RCHO + NADH + H+

39
Q

Fusel Oil

A

nonethanol alcohols

40
Q

Aldehyde Dehydrogenase (ALDH)

A
  • in cytosol and endoplasmic reticulum, same tissue as ADH

- product is less toxic carboxylic acid

41
Q

Antabuse

A
  • treats alcoholism
  • inhibits ALDH
  • aldehyde accumulation and causes illness like hangover without other effects of EtOH
  • resembles -COO- and ALDH is occupied. Retains high affinity
42
Q

Phase I hydrolysis

A

Catalyzed by carboxylesterases in tissues and cholinesterases in plasma

  • RCOOR’ + H2O = RCOOH + R’OH
  • Similar for S and N, replace carbonyl O, same enzyme but fastest with carboxyester
  • know the arrow pushing
  • nonzero rate without enzyme, can occur abiotically
43
Q

Reductive Dehalogenation

A

RX = RH + HX

  • decrease persistence of organochlorine/bromine
  • C-Cl bonds are extremely stable
  • reductive dehalogenation is extremely SLOW
  • microbially mediated - anerobic (human gut, sediment under water)
44
Q

PCBs

A

polychlorinated biphenyls

  • used in electrical insulators
  • persist for decades
  • 209 congeners
  • low Kow
45
Q

Reductive dehalogenation conditions

A

anerobic
human gut
sediment-under water, lower rate of oxygen diffusion (consumption>supply)
Accumulation of organics in the sediment

46
Q

PBDE

A

polybrominated diphenyl ethers
flame retardants
low Kow
similar to PCB in reductive dehalogenation process

47
Q

Global Distillation

A
  • organohalogens have a low volatility but it is not zero
  • evaporate over time and circulate
  • Deposit in arctic because air is cold
  • high accumulation is polar bear
  • high fat content in polar bear milk and gets passed to cubs
  • native women are warned against breastfeeding
48
Q

Glucuronidation facts

A
  • glucuronosyl transferase puts glucuronic acid on a polar functional group (-OH, NH2, COOH)
  • enzyme in microsomal fraction of liver, kidney, GIT
  • products subject to elimination with polar waste or active transport into bile
49
Q

Glucuronidation reaction

A
  • glucuronic acid carrier by an energetic compound (uridine-5-diphosphoglucuronic acid (UDPGA)
  • ROH + UDPGA = RO-GA + UDP
  • reversed by abiotic acid hydrolysis
  • beta-glucuronidase: enzyme produced by gut flora
  • enterohepatic circulation (increase half life)
50
Q

Sulfate conjugation

A

similar to glucuronidation

  • ROH + PAPS + SULT = RO-SO3- + H+ + PAP
  • PAPS - 3 phosphoadenosine-5 phosphosulfate
  • SULT - sulfotransferase
  • elimination with polar waste or active transport in kidney
51
Q

Phase I to Phase II info

A

Phase I - powerful oxidation that produces reactive metabolites
Phase II - ready to works and is used immediately
- energized mechanism
- must work immediately because phase I metabolite is reactive

52
Q

Gluthione conjugation

A

must have a reactive center on the substrate(electrophilic carbon)
gluthione is a nucleophile

53
Q

Gluthione(GSH)

A

polypeptide
gamma-glutamyl-cysteinyl-glycine - high conc in liver, up to 10% of cellular protein, in cytoplasm
SH nucleophilic center
doesnt need enzyme
Rate increases with glutathione-S-transferase (GST)

54
Q

Gluthione mechanism

A

RX + GSH = RSG
mercapturic acid is excreted
remove glutamate and glycine, then acetylate the N

55
Q

Acetylation and Methyltransferases

A

Acetylation catalyzed by N-acetyltransferase
-adds CH3CO to N
Methyltransferases
-N, O and S methyltransferases
-Co-Substrate is S-adenosylmethionine
-HG2+ + MeHg+ = Me2Hg is nonpolar and accumulates lethal at extremely small doses
-methylate 3 amine to make 4+ amine and increase solubility

56
Q

Ultra short lived metabolites

A
  • bind to the enzyme that created them
  • suicide substrate - piperonyl butoxide binds to P450 and decreases their activity, not toxic alone
  • enzyme degradation
  • new enzyme synthesis
57
Q

Short Lived metabolites

A

-react close to where they are generated, dont make it beyond the cell or tissue

58
Q

acetaminophen metabolites

A
  • metabolism occurs by P450, sulfation, and gluceronidation
  • P45O metabolite from acetaminophen is NAPQI which has toxic reaction with proteins and nucleic acids
  • GSH conjugation metabolizes NAPQI
  • Chronic EtOH abuse increases P450 activity and NAPQI increases, but GSH is limiting reagent and gets locally depleted
  • liver cells die and release contents which can be toxic to other cells and kill them
59
Q

Long lived metabolites

A
  • transported systemically
  • methanol CH3OH - CH2O - CHOOH (formic acid)
  • formic acid travels to the eye and causes edema which causes blindness
60
Q

Enzyme induction

A

increases enzyme production

  • DNA-RNA-ribosome-proteins
  • transcription-translation-synthesis
  • inducers are often substrates for P450 and increase P450 production
  • planar and nonpolar
  • EtOH, benzo(a)pyrene, PCBs, PBDEs, dioxins
61
Q

AhR

A
  • Aryl hydrocarbon receptor
  • cytosol
  • complexes inducer
62
Q

ARNT

A
  • aryl hydrocarbon receptor nuclear translocator

- brings complex into the nucleus

63
Q

XRE

A

xenobiotic response element (drug response element)

  • on the P450 gene
  • binding promotes transcription
  • transcription leads to more P450s
64
Q

Ramifications of Induction

A
  • good - facilitates excretion of nonpolar contaminants that would accumulate
  • bad - produces more reactive metabolites (diol epoxides)
65
Q

Biomarkers

A

measurements that indicates an exposure or effect in an organism

66
Q

EROD assay

A

ethoxyresorufin-O-deethylase assay

  • measure P450 activity
  • ethyoxyresorufin is not fluorescent, but resorufin is
  • loe fluorescent levels are detectable advantage over UV-Vis
  • dealkylation of ethyoxyresorufin to resorufin
67
Q

Bioavailability

A

fraction of a total exposure that can be taken up by an organism

68
Q

How to measure toxicant in environment

A
  • EROD assay measures effect, not just exposure, P450s are active
  • integrates exposure over time
  • in vitro test with a liver sample
  • Blood/fat samples tell amount but not effects
69
Q

Renal elimination

A
  • water soluble compounds
  • Phase II metabolites
  • -active transporters
  • -anion/acid transporters (ionized carboxylic acids)
  • -cation/base transporters (ionized amine bases)
70
Q

Liver elimination

A
  • bile acts as a surfactant (hydrophobic and hydrophilic sides)
  • active transport can remove chemcials from blood into bile, inot intestine and feces
  • compounds can be subject to enterohepatic circulation
71
Q

Respiration elimination

A
  • relevant for permanent gases and compounds with high vapor pressure
  • EtOH, solvents
72
Q

Milk

A

Human - 4% (same as cow)
Polar Bear - 30-35%
Human health hazard for persistant organic pollutants (POPs)

73
Q

Non-mammalian pathways

A
  • skin shedding or molting
  • -birds and reptiles
  • leaf fall and fruit production

Toxicology (9 decks)

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