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Toxicology > Toxicology - deck I > Flashcards

Toxicology - deck I Flashcards

1
Q

Xenobiotic

A

is a foreign, potentially harmful, substance, strange for life or for an organism
* that either is not normally naturally produced
* or not expected to be present within that organism,
but still found in this particular organism

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2
Q

mutagenicity

A

is a term used to broadly describe the property of chemical agents or drug substances to induce genetic mutation

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3
Q

teratogenicity

A

the ability to cause defects in a developing fetus

A teratogen is anything a person is exposed to or ingests during pregnancy that’s known to cause fetal abnormalities.

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4
Q

define toxicant and toxin

A

The term “toxicant” denotes, above all, a synthetic substance causing adverse health effects.

A similar term “toxin” usually refers to any proteinous poison produced by a living organism.

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5
Q

define zootoxin

A

also known as venom (from Latin venemus)

denotes a poisonous matter (toxin) normally secreted by snakes, scorpions, bees, and the like.

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6
Q

what is ADME

A

is an abbreviation in pharmacokinetics and pharmacology for “absorption, distribution, metabolism, and excretion/elimination”, and describes the disposition of a pharmaceutical compound within an organism.

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7
Q

what element contributes to DDT’s toxicity?

A

the 5 chlorine atoms in a DDT molecule = very bad

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8
Q

Exposure to (contact with) the toxicant can be one of what 4 options

A
  • acute: contact time with substance (toxicant) shorter than 24 hours, mostly once
  • subacute: usually repeated contacts during 1 month
  • subchronic: contact time 1-3 month, or
  • chronic: contact time longer than 3 months. Usually everyday contact with food.
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9
Q

Dose is usually expressed in

A

micrograms (µg) or milligrams (mg) per kg of body weight (bw)

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10
Q

NOAEL

A

(no-observed-(adverse) effect-level) – the highest dose/concentration, not causing any adverse-toxic effect in any animal in a test group

NOAEL is the basis for the counting of acceptable daily intakes (ADI) and tolerable daily intakes (TDI)

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11
Q

LOAEL

A

the lowest observed [adverse] effect level – the lowest dose causing an observable effect, at least in a portion of the animals.

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12
Q

Absolute (LD100), minimal (LDmin) and median (LD50) LDs can be distinguished.

what are these

A

LD stands for lethal dose

In experimental toxicology, LD50, causes the death of 50% of animals of a test group at an acute contact with a toxicant.

LD100 belongs to the most durable animal and
LDmin to the weakest animal.

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13
Q

what are LC50, LC100 and LCmin

A

LC stands for lethal concentration

Instead of doses, sometimes concentrations in blood plasma are used – the respective parameters will be LC50, LC100 and LCmin (mmol/l, μg/m3).

So LC100 meaning the concentration at which 100% of test group animals die.

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14
Q

ED50

A

effective dose that evokes 50% of the possible alteration of the parameter

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15
Q

IC50

A

IC stands for inhibitory concentration

The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function.

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16
Q

ADI

A

Acceptable Daily Intakes (typically for food additives)

ADI is the quantity of a chemical compound that an individual can consume daily during all their lifetime without any harm to health.

Analogical number for food contaminants is tolerable daily intake (TDI)

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17
Q

explain how Doses can be either external or internal

A

In toxicological studies, the net amount of a compound administered per kg of the test animal weight is regarded as the external dose.

Most substances will cause the toxic effect only after they have been absorbed into the general bloodstream.
The absorbed part of the external dose is called the absorbed or internal dose.

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18
Q

define bioavailability

A

Bioavailability is the fraction of the administered external dose, that reaches the systemic circulation in unchanged form.

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19
Q

transcytosis

A

is a type of transcellular transport in which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side.

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20
Q

what types of compounds begin to absorb in the mouth already?

A

Ethanol, hydrocarbons and other neutral non-ionizable substances

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21
Q

Weak acids diffuse across the membrane best of all in the

A

stomach

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22
Q

Weak bases pass the membranes in the?

A

intestines, where pH ≈ 6.

basic compounds have positive charge

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23
Q

A lipid-soluble non-ionizable substance absorbs where?

A

equally well in any part of the digestive tract, its absorbtivity increases by an increase in the Kow, that is, the lipophilicity of the substance.

This rule does not apply for very lipophilic (Kow > 3000) molecules that tend to form supramolecular colloidal solution in the stomach and intestines, the dispersed
particles of which, micelles, are too large to cross the membranes.

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24
Q

Metals are absorbed mainly in the

A

first part of the small intestine – Cr, Mn, and Zn in the ileum; Fe, Cu, Hg, Th and Sb in the jejunum

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25
Q

Metals may, during absorption, change their

A

valence form:
for example, divalent (ferrous) iron can be oxidized into trivalent (ferric) iron,

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26
Q

Once a substance is in the bloodstream, it or its metabolites may be (4)

A
  • distributed between tissues,
  • excreted from the organism,
  • or contrarywise accumulated in a tissue,
  • biotransformed into different metabolites;
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27
Q

Distribution of xenobiotics in the organism is a dynamic process, depending on

A
  • the ratio of the rates of absorption, metabolism and elimination (excretion),
  • on the physical and chemical properties of the substance,
  • and on the particular environment in various body compartments.
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28
Q

Knowing substance concentration in plasma, it is possible to calculate important pharmaco- or toxicokinetic parameters such as, (4)

A
  • half-life,
  • area under the curve,
  • volume of distribution
  • body burden.
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29
Q

Half-life (τ1⁄2) is

A

the time, during which one half of the initial dose of a substance becomes either degraded, metabolized, or eliminated from the organism.

Is determined by metabolism and excretion rates.

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30
Q

Area under the curve (AUC) is

A

the area in a plot of concentration of a xenobiotic in plasma (y-axis) against time (x-axis). AUC has the unit (mass/volume) × time and expresses the total amount of a xenobiotic absorbed by the body, irrespective of the rate of absorption.

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31
Q

Volume of distribution VD (litres) is

A

the volume of body liquid in which a foreign compound is distributed.

If a toxicant is distributed only in blood plasma, low VD will result,
but if distributed in all body fluids, or concentrated (accumulated) in some solid
tissue, such as adipose tissue, VD will be high.

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32
Q

Body burden is the

A

total amount of the foreign compounds that are present in a body at
a given point in time.
Sometimes, it is also useful to consider the body burden of a specific single chemical, like lead, mercury, or dioxin.

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33
Q

Toxic effect of a compound can be caused either by: (3)

A
  • The parent compound
  • Metabolites, formed at the site of entry into the organism and/or in the liver that are
    sufficiently stable to reach target organs (systemic toxicity)
  • Metabolites, formed in the target organ
34
Q

Biotransformation of xenobiotics is mainly carried out in the

A

liver,
but also in intestinal epithelium, kidneys, lungs, brain, and skin

35
Q

the Liver and kidneys together contain more than 90% of the

A

metabolic activity of an organism

which determines the speed of elimination of the xenobiotic and its bioavailability.

36
Q

Xenobiotics are metabolized (biotransformed) in the organism in two consecutive phases (simplification)
Phase I involves what?

A

activation of the substrate into a primary metabolite

activation can happen via oxidation or reduction etc. (usually oxidation though)

37
Q

Xenobiotics are metabolized (biotransformed) in the organism in two consecutive phases (simplification)
Phase II involves what?

A

conjugation of the primary metabolite into the secondary metabolite

38
Q

A majority (over 90%) of the Phase I reactions are catalyzed by

A

cytochrome P450 monooxygenase complex
(CYP450 for mammalians/plants and P450 for bacterial species), (EC 1.14.) that:

is a superfamily of mostly membraneous isoenzymes
is a hemoprotein

38
Q

A majority (over 90%) of the Phase I reactions are catalyzed by

A

cytochrome P450 monooxygenase complex
(CYP450 for mammalians/plants and P450 for bacterial species) that:

is a superfamily of mostly membraneous isoenzymes
is a hemoprotein

39
Q

Enzyme superfamily CYP450 is found mostly…?

A

in most of the tissues, but in particularly high concentrations in the liver.

is located on the membrane of the smooth endoplasmic reticulum, but also in
other organelles.

40
Q

how does CYP450 act on a substrate?

A

switches an oxygen atom into the substrate molecule, oxidizing the substance.
In certain cases, CYP or P450 is capable of catalyzing also the opposite reaction –
reduction of a substrate.

requires a helper enzyme

41
Q

what is CYP450

A

an essential enzyme family found in mammals

primarily found in liver cells

42
Q

what is the epoxidation of compounds

A

a conversion of a usually unsaturated compound into an epoxide.

an epoxide is a cyclic ether with a three-atom ring, containing two atoms of carbon and one atom of oxygen

Electrophilic epoxides formed are usually unstable and chemically reactive. They can interact with nucleophilic groups in crucial cellular macromolecules and thereby have a deleterious physiological effect.

43
Q

what is the largest group of the Phase II reactions.

A

Conjugation with glucuronic acid

Respective enzyme is UDP-glucuronyltransferase (UGT) superfamily.
UGT content is highest in liver

44
Q

how can the enterohepatic circulation increase exposure time to xenobiotics

A

glucuronides (so metabolites) of xenobiotics are transported to the intestines with the bile.
after hydrolysis of the glucuronide by microbial β-glucuronidase in the intestines,
enterohepatic circulation reciruclates the metabolites lengthening their half-life in plasma essentially enhancing exposure time of the target organs like liver.

Toxicity increases.

45
Q

Hydrolysis of esters and amides is catalyzed by

A

esterases, a group of enzymes, characterized again by a broad substrate
specificity.

The conversion of both types of substrates is actually catalyzed by the
same enzymes.

The esterases accomplish numerous endogenous functions in the organism
but they are also able to metabolize foreign compounds.

46
Q

esterases are historically divided

A

A, B and C-esterases.

According to reactivity with toxic organophosphorus compounds,
either as with substrate (A), as with inhibitor (B) and no reactivity(C).

47
Q

Toxicity of the well-known organophosphorus and carbamate insecticides is based on

A

the inhibition of acetylcholinesterase, belonging to the B-esterases.

48
Q

what are epoxides

A

Epoxides are mostly electrophilic molecules with a very reactive triangular oxirane
cycle.

The reaction between epoxy-group and other
nucleophiles (like proteins) may also lead to other acute or subchronic damages
(intoxications).

Epoxides are generated from aflatoxins, PAHs, polyunsaturated fatty acids (PUFA)…

49
Q

Epoxide hydrolases are located primarily in the

A

endoplasmatic reticulum, but also in the cytosol of the hepatic cells.

50
Q

The activity of CYP450 in the small intestine is highly dependent on

A

dietary iron. A deficiency in this metal abruptly reduces the activity of several CYP-linked
enzyme

51
Q

what are the two most important regulation mechanisms of an enzyme activity

A

Regulation of xenobiotic metabolism by induction and inhibition

CYP450s are often the rate-limiting enzymes in the metabolic processes, and hence,
have important role in the determination of in vivo kinetics and interactions.

52
Q

what does it mean to be a complementary molecule_

A

matching in dimensions and in charge distribution thus capable of binding

53
Q

Agonists are

A

exogenous substances that also bind to a receptor and activate it.
They imitate the action of endogenous ligands like hormones or neurotransmitters,
but usually weaker.

54
Q

Antagonists are

A

substances that, by binding very strongly and irreversibly to the receptor, inactivate it.

55
Q

what is CYP450

A

enzyme family that plays a huge role in metabolizing things that are foreign to the body like drugs etc. detoxification

the original forms of drugs can’t really be cleared so theyre first converted into a more familiar form via 2 phases for the purpose of excretion

56
Q

Most important cell receptor?

A

AhR
aryl hydrocarbon or dioxin receptor

functions to regulate a battery of genes of CYP
AhR activates a whole gene battery involved in phase I and phase II metabolism.

57
Q

What is the most important route of elimination for xenobiotics?

A

the kidneysn, as 25% of the arterial blood passes through the kidneys, 20% of which is filtrated through glomeruli.

Large molecules like proteins are not able to pass through intact glomeruli
and fat-soluble molecules like bilirubin are reabsorbed from renal tubules.

58
Q

Substances are moved from the blood to the kidneys by one of the following 3 mechanisms:

A
  • Filtration through glomerular pores – small molecules
  • Passive diffusion into renal tubules – fat-soluble molecules
  • Active transport into tubular liquid – separate systems for anions and cations
59
Q

What is para-aminohippuric acid

A

a metabolite of para-aminobenzoic acid

that is used for study of transport of substances in kidneys

transported from blood to renal tubules
by a special anion-transporting system.

PAH clearance is used to measure renal plasma flow

60
Q

What is Ficks law

A

Fick’s laws of diffusion describe diffusion

61
Q

Elimination in the content of bile formed in the liver is especially
important for

A

large polar molecules.

Polar compounds with a molecular weight around 300 Da and
higher, like glutathione conjugates,
are eliminated from the organism by this route.

62
Q

liver has three specific transport systems,
separate for (3)

A

the neutral molecules, anions, and cations.

Saturation of these systems leads to the rise of the content of these substances in the
liver; in the case of a toxic compound, it can cause liver damage.

63
Q

The biliary route of elimination can have these 4 adverse effects

A
  • substantially increase the half-life of a compound
  • lead to the formation of toxic compounds in the intestines
  • increase the exposure of the liver to a toxicant
  • cause serious hepatic damage due to saturation of the excretion system
64
Q

What? has primary control over translocation, metabolism and toxic action
because the total amount of herbicide available for these processes is determined by
the amount of herbicide absorbed by the plant.

A

Absorption has primary control over translocation, metabolism and toxic action
because the total amount of herbicide available for these processes is determined by
the amount of herbicide absorbed by the plant.

65
Q

What is glutathione?

A

is a substance made from the amino acids glycine, cysteine, and glutamic acid. It is produced by the liver and involved in many body processes.

is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals.

66
Q

Metabolism PHASE III related to?

A

Phase III reactions are unique to plants because plants do not excrete xenobiotics or
metabolites as animals do. Plants remove somehow the xenobiotic within their own
system.

67
Q

what does PBTs stand for?

A

Persistent Bioaccumulative Toxic Chemicals

68
Q

Plants store many toxic metabolites also in their –?– and these substances are
released upon herbivore attack.

A

Plants store many toxic metabolites also in their vacuoles and these substances are
released upon herbivore attack.

69
Q

The four main methods for removal of a toxicant from the GI tract are:

A

emetic preparations
gastric lavage
use of absorbents
enema

70
Q

Activated C binds substances by –?–, however does not bind well to certain
chemicals.

A

Activated C binds substances by van der Waals forces, does not bind well to certain
chemicals, including alcohols, glycols, strong acids and bases, metals and most
inorganics (lead, arsenic, fluorine, boric acid).

Due to high degree of
microporosity, 1 g of material has a surface area over 500 m2
(about 1/10 the size of a
football field)

71
Q

Acceleration of elimination of a toxicant from an organism by 2 options.

A

by increasing
urine volume or changing the urine pH.

Method is efficient in case of either acidic or alkaline substances or their metabolites.
Acidic compounds are better soluble at alkaline pH, basic compounds at acidic pH.

72
Q

Urine can be turned more alkaline, for example, by

A

feeding solid sodium carbonate or
by injection of its solution into the vein.

Successful in case of barbiturate or aspirin
intoxications.

73
Q

Urine can be turned more acidic e.g. for amfetamine by administration of

A

ammonium
chloride.

74
Q

sorbent definition

A

A material similar to molecular sieve material, which acts by adsorption (attracting molecules to its surface)

are insoluble materials or mixtures of materials used to recover liquids through the mechanism of absorption, or adsorption, or both.

75
Q

Specific mechanisms of antidote action (3)

A
  1. Antidote as an chelating agent.
  2. Antidote as an accelerator of detoxication of a highly reactive metabolite.
  3. Antidote as a decelerator of a toxicant’s metabolism
76
Q

Explain mechanism: Antidote as an chelating agent.

A

Antidote reacts with a toxicant
forming water-soluble chelate complexes, which are excreted faster
than the parent compound.

77
Q

Explain mechanism:
Antidote as an accelerator of detoxication of a highly reactive metabolite.

A

A good example is N-acetylcysteine, used as the antidote in case of paracetamol
overdoses.

It increases the synthesis of glutathione in hepatocytes;
glutathione effectively binds para-benzoquinone-imine, a dangerous metabolite of
paracetamol, removing it from the complex with a hepatic protein.

78
Q

Explain mechanism: Antidote as a decelerator of a toxicant’s metabolism

A

is used when the metabolite is
more toxic than the foreign substance. Hence, it is reasonable to reduce the
metabolism of the toxicant.

e.g. conversion (oxidation) of ethylene glycol, into toxic
oxalic acid, is reduced by the administration of ethanol. Ethanol blocks the metabolism of
ethylene glycol, enabling elimination of the glycol in the unaltered form.

79
Q

anoxemia and anoxia

A

anoxemia = a condition of subnormal oxygenation of the arterial blood.

anoxia = an absence of oxygen.

80
Q

material cumulation

A

Chronic intoxication develops in the case of either material cumulation or functional cumulation.

Material cumulation being accumulation of a toxic substance in the organism.

In the case of toxic heavy metals (Pb, Hg, Cd, etc.), which have a long half-life in the
organism, mainly material cumulation occurs, although functional also plays a definite
role in the development of an intoxication.

81
Q

functional cumulation

A

Chronic intoxication develops in the case of either material cumulation or functional cumulation.

Functional cumulation being accumulation of initially minute functional alterations in the organism.

Long-term exposure to low doses of phosphororganic inhibitors depresses
cholinesterases to such a low level that symptoms of intoxication start to appear.

Toxicology (6 decks)

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