HLTH 340 Lecture A5W2013 1 HLTH 340 Lecture A5 Toxicokinetic
processes: Distribution (part-2) internal membrane barriers NOTICE:
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prohibited. Slide 2 HLTH 340 Lecture A5W2013 2 Internal membrane
barriers and their effect on tissue distribution of xenobiotics
many organs will permit the distribution of large amounts of
xenobiotic chemicals and drugs from the blood to the tissue many
low-MW dissolved solutes in the blood can enter readily into
perfused tissues (e.g. liver, kidneys, lung, etc.) transcellular
route (lipophiles) paracellular route (hydrophiles) some especially
vulnerable tissues have special protective internal membrane
barriers that restrict the uptake of some xenobiotics from the
blood to the tissue brain: blood-brain barrier (BBB) testis
(seminiferous tubules): blood-testis barrier (BTS) eye (retina):
blood-retinal barrier (BRB) Slide 3 HLTH 340 Lecture A5W2013 3
Internal membrane barriers depend on several different types of
mechanisms the restrictive distribution function of internal
membrane barriers depends on several different types of mechanisms
anatomical barrier endothelial cells of blood capillaries (and
other supporting cells) have tight junctions that prevent
paracellular uptake of xenobiotics (and some endobiotics) from the
blood to the tissue physiological barrier capillary endothelium
cells have selective carrier-mediated uptake channels (facilitated
or active transport) which are specific for beneficial nutrients
and regulatory factors capillary endothelium cells have several
types of efflux pumps (outward active transport) that can remove
many xenobiotics that enter into the tissue via transcellular
permeation internal membrane barriers are not always static or
constant physiological regulation of the tight junctions or efflux
pumps may alter capillary permeability pathological effects of
injury, infection, stress, or toxic chemicals may alter barrier
function development of the membrane barriers in early life
(embryo, fetus, infant) will occur in stages protective barriers
may not be fully mature or functional early in life barrier
function may alter or become less effective with advancing old age
Slide 4 HLTH 340 Lecture A5W2013 4 The blood-brain barrier (BBB)
prevents/restricts the flow of xenobiotics and drugs from the blood
to the brain tissue Slide 5 HLTH 340 Lecture A5W2013 5 Tight
junctions in the capillary endothelium prevent paracellular
permeation across the blood-brain barrier Slide 6 HLTH 340 Lecture
A5W2013 6 P-glycoprotein (P-gp) and related MDR / MRP efflux pumps
expel many xenobiotics at the blood-brain barrier Slide 7 HLTH 340
Lecture A5W2013 7 MPTP toxicity to the substantia nigra (SN) can
selectively induce a form of chemical Parkinsonism MPTP is
selectively toxic to brain neurons in the brainstem substantia
nigra (SN) dopamine (DA) producing neurons in the SN are damaged or
destroyed the projecting DA axons to the basal ganglia can no
longer supply dopamine to the brain motor centers (caudate and
putamen) causes a severe chemical form of Parkinsons disease Slide
8 HLTH 340 Lecture A5W2013 8 Redox trapping (ion trapping) of MPTP
/ MPP + at the BBB via MAO-B oxidation Slide 9 HLTH 340 Lecture
A5W2013 9 Molecular mimicry for polyamine transporter channel
allows uptake of MPP+ and paraquat to target issues (brain, lung) +
MPP + paraquat spermine putrescine + ++ ++ drug metabolite chemical
herbicide endobiotic Slide 10 HLTH 340 Lecture A5W2013 10 Toxicant
entry into the brain across the BBB and toxic interactions with
diverse cell types Slide 11 HLTH 340 Lecture A5W2013 11 DA neuron
uptake of MPP + or agricultural toxicants (rotenone, paraquat)
affects mitochondrial ET chain Slide 12 HLTH 340 Lecture A5W2013 12
Metallic (elemental) mercury Hg o is a liquid metal at room
temperature Slide 13 HLTH 340 Lecture A5W2013 13 Sources of
exposure to mercury and methylmercury in the environment individual
exposures community exposures Slide 14 HLTH 340 Lecture A5W2013 14
Movement of mercury in the environment and metal speciation as Hg
o, Hg 2+ and methylmercury (MeHg) Slide 15 HLTH 340 Lecture A5W2013
15 Mobilization from soil (or ice) and biomagnification of mercury
within the aquatic environment wrong biomagnification in food chain
mobilization chemical transformation atmospheric precipitation
uptake by small biota Slide 16 HLTH 340 Lecture A5W2013 16 Organic
mercury compounds: methylmercury (MeHg + ), ethylmercury (EtHg + ),
dimethylmercury, thiomersal Methylmercury (MeHg) (hydrophilic)
Ethylmercury (EtHg) (hydrophilic) very lipophilic (supertoxic) very
hydrophilic Slide 17 HLTH 340 Lecture A5W2013 17 Molecular mimicry:
methylmercury (MeHg) mimics the methyl sulfur group in the amino
acid methionine CH 3 Hg + + Cys --> CH 3 Hg-S-Cys + MeHg +
cysteine --> cysteinyl methylmercury (~ mimics methionine) S Pb
S Slide 18 HLTH 340 Lecture A5W2013 18 Transport of methylmercury
(CH 3 Hg + ) as a methionine mimic across the BBB via the system L
transporter (LAT1, LNAA) luminal side (blood) abluminal side
(brain) Slide 19 HLTH 340 Lecture A5W2013 19 Transport of
methylmercury (MeHg) and possibly ethylmercury (EtHg) across the
BBB by LAT1 channel MT1a = metallothionine MTF1 = metal regulatory
transcription factor 1 LAT1 = large aminoacid transporter 1 DMT1 =
divalent metal transporter 1 Slide 20 HLTH 340 Lecture A5W2013 20
Exchange and sequestration reactions of methylmercury within target
cells (e.g. brain neurons) selenium-containing proteins (with
selenocysteine residues) react irreversibly with MeHgSR molecules
(protective sequestration reactions) sulfur-containing proteins
(with cysteine residues) are molecular targets that react by
exchange with MeHgSR molecules (mercury exchange reactions) uptake
of MeHgSR molecules via LAT1 transporter channel (methionine
mimicry) Slide 21 HLTH 340 Lecture A5W2013 21 Mercury and lead and
the risk of fetal toxicity during early human development
