Lecture 4: Disposition Flashcards
what are the four components of the disposition of a toxicant?
absorption
distribution
biotransformation
elimination
______ = when toxicants cross membranes and enter the bloodstream or
lymphatic system
Absorption
Toxic effects may be ____ (in a specific tissue) or ______ (throughout the
organism)
local
systemic
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
what kind of compounds can freely diffuse across the cell membrane?
lipophilic (hydrophobic) compounds
T/F: Toxicants often need to diffuse through tissues before entering the bloodstream
true!
______ 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
______ diffusion: diffusion of
toxicants in between cells
Paracellular
what are the two main ways a toxicant can pass through membranes?
passive transport
transporter mediated
T/F: Toxicants vary in how lipophilic they are
true!!! * Rate of transport across membranes correlates with their lipid solubility
what are the two main categories of passive transport?
diffusion and filtration
______: 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
what are the two main categories of transporter mediated transport?
active transport
facilitated diffusion
what is the main difference between active transport and facilitated diffusion?
active transport requires ATP
why does active transport require ATP?
moving solutes AGAINST their concentration gradients
can active transporters become saturated?
yes! they can reach a maximum
what do we use ATP binding cassette transporters for?
active transport
what do we use solute carriers for?
facilitated diffusion
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”
what is the difference between pinocytosis and phagocytosis?
pino: liquids
phago: solids
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)
In ________,
cells have receptors that recognize
certain proteins and form a vesicle
receptor-mediated endocytosis
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
β
what are the main sites of absorption?
GI tract
lungs
skin
________ 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!
