Lecture 4: Disposition Flashcards by Zoe Phillips

what are the four components of the disposition of a toxicant?

absorption
distribution
biotransformation
elimination

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______ = when toxicants cross membranes and enter the bloodstream or
lymphatic system

Absorption

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Toxic effects may be ____ (in a specific tissue) or ______ (throughout the
organism)

local
systemic

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what four layers must a toxicant pass through to reach target organ/tissue?

stratified layers of skin’

thin cell layers of epithelium of the lungs and
gastrointestinal tract

the capillary endothelium (into and out of
bloodstream)

cells at the target organ or tissue

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what kind of compounds can freely diffuse across the cell membrane?

lipophilic (hydrophobic) compounds

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T/F: Toxicants often need to diffuse through tissues before entering the bloodstream

true!

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______ diffusion: diffusion of
toxicants through cells (must pass through cellular membranes). Often
occurs if the cells are packed tightly with little space between them

Transcellular

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______ diffusion: diffusion of
toxicants in between cells

Paracellular

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what are the two main ways a toxicant can pass through membranes?

passive transport
transporter mediated

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T/F: Toxicants vary in how lipophilic they are

true!!! * Rate of transport across membranes correlates with their lipid solubility

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what are the two main categories of passive transport?

diffusion and filtration

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______: When blood plasma is forced out of capillaries through pores
because of pressure, small molecules can move with it

filtration

one of the forms of passive transport! keeps big molecules inside blood

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what are the two main categories of transporter mediated transport?

active transport
facilitated diffusion

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what is the main difference between active transport and facilitated diffusion?

active transport requires ATP

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why does active transport require ATP?

moving solutes AGAINST their concentration gradients

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can active transporters become saturated?

yes! they can reach a maximum

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what do we use ATP binding cassette transporters for?

active transport

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what do we use solute carriers for?

facilitated diffusion

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Fish need to maintain the production of ATP by increasing their ______ to
maintain sufficient O2 delivery to tissues. Some of this ATP is needed to fuel
active transporters to move the toxicants out of the cells!

“breathing”

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what is the difference between pinocytosis and phagocytosis?

pino: liquids
phago: solids

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T/F: Larger toxicants can enter cells through
endocytosis

true! this is more common for large molecules like protein toxins (ricin, botulinum toxin, cholera toxin)

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In ________,
cells have receptors that recognize
certain proteins and form a vesicle

receptor-mediated endocytosis

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Protein toxins are often heterodimers made of the toxin (α subunit) and multiple β subunits. The ____ subunit binds to membrane components and causes the cell to take in the toxin

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what are the main sites of absorption?

GI tract
lungs
skin

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________ of drugs includes all routes involving the alimentary canal * i.e., Sublingual, oral, rectal

Enteral administration

_______ of drugs includes all other routes i.e. injection

Parenteral administration

T/F: if an injection is intravenous, it eliminates absorption

true! because we're already putting it directly into the bloodstream

what are the four ways to inject something?

intramuscular subcutaneous intravenous intradermal

which part of the GI tract absorbs nutrients (also toxicants)

small intestine

how do most toxicants enter from our GI tract?

through diffusion! there are few actively transported in GI

T/F: Diffusion is proportional to the surface area (i.e., villi and microvilli) and residency time.

True!! Probability of absorbing a toxicant increases the longer it stays in the intestine

Chemicals absorbed in the GI tract first go through the liver via the ______

hepatic portal

the _______ is a major site for detoxification, also a target tissue for many toxicants!!

liver

the ______ Can selectively excrete toxicants into bile

liver

where do we intake the most water? also some toxicants

large intestine

T/F: Natural gut bacteria can convert toxicants to different forms in the large intestine

true!! they can become more or less toxic

T/F: Acidity of the stomach helps with the absorption of weak acids

true!

The ______ are a major site of absorption for gases, vapors of volatile liquids and aerosols

lungs

how do gases and vapours get into the bloodstream?

gas want to diffuse to equilibrium from air to blood, so when inhaled, they enter blood and are distributed throughout the body... then transferred to target tissues blood continually picks up more gas at the lungs, this happens until gas is in equilibrium throughout the body

T/F: Each gas/vapor has its own properties that indicate how quickly equilibrium is reached

true size is a big parameter for absorption!

what is the difference between an aerosol and particulate

aerosol: droplet of liquid particulate: chunk of matter

T/F: Deposition of aerosols depends on the size

true! depending on how big they are, they get stuck in different places

how many particles are swept away by cilia each day?

only around 20% some particles can hang around for months-years

T/F: The skin is relatively impermeable, so it is a minor route of toxicant absorption

true

once a toxicant has entered the bloodstream is must be...

distributed!

T/F: Different toxicants can be stored at different sites in the body depending on their properties. Storage sites aren’t always the target of toxicity!

true!

what is albumin?

a sticky protein in the blood, abundant! usually transports fats, hormones, and hydrophobic compounds can also bind toxicants! reversible process

____ and ___: Involved in the metabolism and excretion of toxicants, but can also be a site of storage

liver and kidney

______: Many toxicants are hydrophobic, so can accumulate in adipose tissue.

fat

what happens when carbs are depleted and we have toxicants stored in our fat tissue?

fat breaks down and toxicants from fat storage are released into bloodstream! can be dangerous

In the Netherlands in the 1970s, female ducks were dying when laying eggs. what was happening to them?

it was from dieldrin poisoning (an organochloride pesticide!) when their fat reserves were used to produce eggs, it was released and reached toxic levels in the mother ducks

what keeps toxicants out of the brain?

blood brain barrier

how does the blood brain barrier keep toxicants away from brain?

The capillaries in the brain have few pores, which can limit diffusion. The capillary endothelial cells have MDR transporters that can send unwanted compounds back into the bloodstream. Paracellular diffusion limited (transcellular can be more regulated)

T/F: the BBB evolved to keep natural toxins out of our brains!

true!

T/F: Very hydrophobic non-ionic chemicals can readily pass the BBB though… * Just like the caffeine that goes directly to my brain!

true!

T/F: The BBB is poorly developed in infants, which also makes them more susceptible to toxicants

true!

_______ is the metabolic conversion of toxicants in the body

Biotransformation

why is the liver the main site of detoxification?

because its the first place toxicants are taken to!

Enzymes involved are typically divided into four categories based on what they do to the target compound: what are they?

1) Hydrolysis 2) Reduction 3) Oxidation 4) Conjugation

T/F: The presence of versions of enzymes can be different between species as well as the genetic sequence can be different between individuals and populations

true things get complicated quick!

T/F: Biotransformation of toxicants can change with age - can also decline in seniors

we're not great the younger, and older, we are

Many toxicants are hydrophobic, therefore biotransformation converts the compound to a _______ form to facilitate transport out of the cell and the body

hydrophilic

what are the three general stages of biotransformation

phase one: modification phase two: conjugation phase three: exported out of cell

whats another reason we want to biotransform a toxicant into hydrophilic compounds

makes the toxicant unable to diffuse across the membranes uncontrolled

phase ____: Caused by enzymes that are either constitutively expressed (i.e., all the time) or induced by exposure to a class of toxicant

one of biotransformation

how many phase I enzymes are there?

at least 22 can take place in different parts of cell!

A modification of the compound often by exposing or introducing a - OH (hydroxy), -NH2 (amine), -SH (thiol), or -COOH (carboxyl) through: * Oxidation * Reduction * Hydrolysis why do we do this in phase I of biotransformation?

to introduce polar groups that can then be conjugated in phase 2

Most common Phase I enzymes are

cytochrome P450 enzymes (CYPs or P450s)

what do CYPs do?

oxidate compounds

______: Heme containing enzyme that adds 1 oxygen molecule to a substrate * (i.e., the toxicant). * Highest concentration in the liver, but found in almost all tissues

cytochrome P450s

T/F: Animal P450s can catalyze reactions on many different compounds (toxicants and endogenous molecules) – very large family of enzymes

true! humans have 57 CYP genes, which encode different enzymes

CYP2D6 demethylates ______, which converts it to the active form of morphine

codeine

why does drinking grapefruit juice alter some pharmaceutical uptake and metabolism?

contain bergamottin and dihydroxybergamottin which inhibit some human CYP450s

______: Reactions where toxicants (often Phase I metabolites) are conjugated with or coupled to endogenous compounds to create more hydrophilic metabolites for excretion

phase II biotransformation

what are the major phase II reactions?

Glucuronidation (uses glucuronosyltransferase) Sulfonation (uses sulfotransferase) Conjugation with glutathione (Glutathione-S-Transferases) Conjugation with amino acids Acetylation Methylation

With the exception of _______, most Phase II enzymes are located in the cytosol

glucuronosyltransferases these are found in microsomes!

_______- When something is converted into a more reactive molecule

metabolic activation

T/F: Biotransformation Can Lead to a Toxic Metabolite

true!

The “_______” stage refers to the transport of the metabolites out of the cell

Phase III

which three main types of transporters do we use in phase III biotransformation?

ABC transporters (7 families) MRD/MDRs Solute carriers (52 families!)

T/F: excretion can be from excretion AND/OR biotransformation

true! our liver eliminates a LOT for us!

_______: Toxicants are excreted into urine in the kidneys through glomerular filtration, and passive and active transport. * Toxicants that move via filtration and are polar or in ion form are excreted in urine. * Some less polar toxicants may diffuse into the kidney lumen

urine excretion

Many types of toxicants may move into the kidneys using transporter mediated mechanisms... what are the two examples?

* OATs * MRP/MDRs

T/F: Bile is the most important contributing source of toxicants to fecal excretion

true! toxicants metabolized in the liver can be moved directly to the bile for excretion into intestines

do we use active transport mechanisms to move toxicants from bile into intestines

yes! transporters move compounds into liver where biotransformation occurs then actively transport into bile

T/F: Some toxicants may move from the blood into the intestines

true

T/F: some toxicants will be biotransformed by gut flora in intestines

super true! this tends to favour reabsorption though

what are four other routes of excretion (only two are main ways):

exhalation breast milk sweat/saliva- minor roles

________: the study of models and mathematical descriptions of the time course of disposition of a clinical drug in the whole organism

Pharmacokinetics toxicokinetics used when specifically examining toxicants

_________: incorporates the physiology of the animal into models and tends to enhance predictions of tissue accumulation

Physiologically-based toxicokinetic (PBTK) model

why are PBTK models so great?

animal-free risk assessment! no bioassays!