HLTH 340
Lecture A3
Toxicokinetic processes:
absorption (part-2)
carrier-mediated transport
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Carrier-mediated absorption
using membrane transport channels
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membrane transport channels
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2 types of membrane transporter channels
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active transport channels
facilitated diffusion channels
active transport
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large glycoprotein molecules embedded in the phospholipid membrane
act as channels (pores) that allow specific hydrophilic solutes (e.g. metal ions) to cross
membrane barriers
enables transcellular absorption of many hydrophilic ions and polar molecules
increases rate of absorption
can concentrate (or remove) substance in tissues against a concentration gradient of a
given solute (non-equilibrium; pumps solutes ‘uphill’)
requires energy source (e.g. ATP or other source of chemical energy)
facilitated diffusion (passive transport)
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increases rate of absorption
does not concentrate or eliminate substance in tissues (equilibrium only; no pumping)
no energy source required
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Types of transcellular membrane transport
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Absorption of inorganic ions through
membrane ion transport channels
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each type of channel has a selective preference for transporting certain ions
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specific solutes are preferred, but not absolutely specific
factors determining ion transporter specificity include
• ionic radius(size)
• positive or negative charge
• valency of the ionic charge
• class of metal ion (alkaline metals, transition metals, heavy metals)
size and ionic charge determines selective transport thru ion channels
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cation transport channels (K+, Na+, Ca++, etc.)
transport positively charged ions (e.g. metals)
monovalent (+1), divalent (+2), trivalent (+3), etc.
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anion transport channels (Cl-, I- , ClO3- etc.)
transport negatively charged ions
monovalent (-1), divalent (-2), trivalent (-3), etc.
factors affecting rate of transport
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affinity (high-affinity ==> rapid transport) <-- determined mainly by ionic charge and the effective ionic radius
saturation (rate-limiting factor for absorption speed)
competition (2 substances compete for the same transporter channel)
regulation (up-regulation or down-regulation by other physiological factors)
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Metal speciation
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metals can exist in different physico-chemical states (species)
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elemental (metallic)
oxidized (metal oxides and salts)
inorganic or organic compounds
metal speciation
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inorganic metals can have several different oxidation states
elemental (metallic) species, Meo
neutral, no electric charge
solid metal (e.g. Pbo) or metal vapor (e.g. Hgo )
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oxidation states: loss of electron (LEO) is chemical oxidation
Me+
Me++
Me+++
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different species of the same metal can vary widely in toxicity
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loss of 1 electron is valence state (I)
loss of 2 electrons is valence state (II)
loss of 3 electrons is valence state (II)
example: chromium:
Cr-III (chromium three) -- oxidation--> Cr-VI (chromium six)
low toxicity
high toxicity
organometallic compounds
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metal atom covalent linked to organic (carbon chain) group(s)
frequently very toxic
lipophilic organometal compounds are especially hazardous
example: mercury
mercuric ion (Hg2+) --> methyl mercury (organic)
low toxicity
high toxicity
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Metal ions - ‘heavy metal’ ions compete for
membrane transport via ionic mimicry
precious metals (toxic, but rare)
essential metals
trivalent metals
(too ionic or insoluble to be absorbed)
toxic metals
heavy metals
(ionic mimicry)
transition metals
(absorbed via
transport channels)
alkali metals
(absorbed via
transport channels)
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Intestinal calcium transport channels:
calcium (Ca++) uptake competes with lead (Pb++)
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intestinal epithelium contains selective ion transport channels for different divalent cations (Ca++, Fe++, Zn++)
– each serves as a transcellular transport channel of divalent cations from the intestinal lumen into the bloodstream
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example: calcium (Ca++ )
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TRPV6 (ECaC2) calcium channel
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calcium is an essential metal nutrient
paracellular uptake by passive diffusion is sufficient at high dietary calcium levels(strong conc gradient)
transcellular carrier-mediated transport is required for low dietary concentrations of calcium
Ca++ uptake requires transcellular transport via a selective divalent cation calcium channel
requires ATP energy to run the active transport system (pump)
selective calcium absorption occurs from many foods (milk, dairy products, vegetables, fruits, fish)
Ca++ is absorbed from the intestine to blood using indirect active transport via the TRPV6 calcium channel
epithelial calcium channel type 2 (ECaC2; now termed TRPV6)
carrier-mediated uptake by TRPV6 is up-regulated by active vitamin D
1, 25-(OH)2 D3
• sunlight / UV synthesis / melanization
• vitamin D supplements in milk and other diary products
also sustained by estrogen hormones (up-regulation)** **ocurs only in females
lead (Pb++ )
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lead exists as a divalent cation (Pb++) -- the ion structure of lead mimics calcium ion (ionic mimicry)
Pb++ is absorbed from the intestine into the blood using same Ca++ transport channel (TRPV6 )
saturation-competition occurs with calcium versus lead for saturable TRPV6 channels in intestine
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Carrier-mediated transport is a saturable process that has
a limited capacity to move solutes
paracellular intestinal
calcium absorption
at high Ca++ conc
(passive diffusion)
TRPV6 transport
channel becomes
saturated at high Ca++
conc
TRPV6 intestinal
calcium absorption
at low Ca++ conc
(carrier-mediated)
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Calcium ion transport channel embedded in epithelial
cell membrane (TRPV6)
Pb2+
Ca2+
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Organized water ionic groups and polar groups
effective ionic radius - ionic molecules and metal ions
form electrostatic bonds with the surrounding water
molecules, so that the ions actually have a much larger
sphere of hydration than the notional size of the
unhydrated metal ion -- the radius of the sphere of
hydration determines the degree of penetration of the
metal ion through a specific carrier-mediated transport
channel
hydrogen bonding - in hydrophilic polar molecules, the
hydrogen in one or more functional groups (e.g. -OH)
has a slight positive charge and is therefore attracted by
the partly negatively charged oxygen of a nearby water
molecule, with the result that a hydrogen bond is
formed.
The dissolved (solute) molecules and the
water molecules thus become linked to one another.
When non-ionic polar molecules form hydrogen bonds
with the surrounding water molecules, the polar
molecules are ‘glued’ to the water solvent layer -- this
organized water layer must be stripped away before the
solute molecule can penetrate through a narrow carriermediated transport channel
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Ion transport channels - the effective ionic radius of
hydration sphere for divalent cations
effective ionic radius - for ionic radius of metal divalent cations, the smaller ions
have higher ionic potentials and form stronger bonds with water molecules, so that
smaller ions actually have a larger sphere of hydration when entering into a specific
ion transport channel
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Structure of the TRPV6 (ECaC2) tetrameric calcium
channel using molecular modeling
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Cation transport channel (TRPV6) for calcium ion:
absorption in the intestinal epithelium
anti
porter
channel
Pb++
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ATP
-dependent
channel
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Absorption pathways for lead permeation from the intestinal
lumen through the enterocytes
TRPV6
(Ca++)
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DMT-1
(Fe++)
transcellular
ZIP-1
(Zn++)
paracellular
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Lead (Pb): a heavy metal toxicant that is a common
environmental health hazard
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4 major toxic heavy metals are of common concern in environmental health
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major environmental sources of lead
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IQ reduction and subtle mental retardation
hyperactivity and behavioral disorders (maybe??)
prevention of chronic lead poisoning -- (1) infants (2) pregnant women (3) elderly
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leaded paints (lead oxide PbO) -- houses built before 1978
auto exhaust in soils (PbCO3 from leaded gasoline) -- leaded gasoline additive (tetraethyl lead) until 1976
pica in young children (PbO in house dust, paint chips)
lead contamination dust (industrial and lead smelter neighborhoods)
lead drinking water pipes in older neighborhoods/houses
chronic exposure to very low levels of lead (~10 ug/dL??) can cause
permanent neurologic damage in children
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lead
mercury
cadmium
arsenic
calcium supplements (BEWARE!)
diet with dairy products, high protein intake, adequate vitamin D
estrogen supplements in post-menopausal women??
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Pathological features of lead poisoning
in adults and children
In the adult, the brain and central nervous
system are relatively less vulnerable to the
toxic effects of lead because the adult brain
is biologically matured and does not undergo
developmental retardation as is the case for
infants and young children.
Therefore many adults may experience other
health effects such as chronic anemia,
hypertension, or kidney malfunction.
In children the main effect is neurological
(impaired brain development).
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Speciation of lead (Pb) in the environment
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Causal pathways of lead exposure and health effects DPSEEA framework
D
P
S “stressor”
E “exposure”
E “effect”
A
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Lead pipe replacement programs can lead to elevated lead
in home drinking water supplies
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Effects of lead poisoning in children
related to blood lead levels (ug/DL)
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Potential effect of chronic lead poisoning on the
intellectual development of young children
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Effect of ethnicity (race) on percentage of children
with blood lead conc > 10 ug/dL
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Relationship between population poverty
and % living in high-risk housing for lead exposure
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Lead exposure patterns in neighborhoods
close or distant to arterial roads
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Effect of phase-out of leaded gasoline
in the 1970’s (United States)
regulatory lead levels
(ug/dL in blood)
observed lead levels
< 2 ug/dL?
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