Transcript Lecta5 - University of Waterloo

HLTH 340
Lecture A5
Toxicokinetic processes:
Distribution (part-2)
internal membrane barriers
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HLTH 340 Lecture A5
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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
–
–
–
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brain: blood-brain barrier (BBB)
testis (seminiferous tubules): blood-testis barrier (BTS)
eye (retina): blood-retinal barrier (BRB)
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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
–
–
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protective barriers may not be fully mature or functional early in life
barrier function may alter or become less effective with advancing old age
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The blood-brain barrier (BBB) prevents/restricts the flow of
xenobiotics and drugs from the blood to the brain tissue
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Tight junctions in the capillary endothelium prevent
paracellular permeation across the blood-brain barrier
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P-glycoprotein (P-gp) and related MDR / MRP efflux pumps
expel many xenobiotics at the blood-brain barrier
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MPTP toxicity to the substantia nigra (SN) can selectively
induce a form of “chemical Parkinsonism”
•
•
•
•
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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 Parkinson’s disease
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Redox trapping (ion trapping) of MPTP / MPP+
at the BBB via MAO-B oxidation
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‘Molecular mimicry’ for polyamine transporter channel allows
uptake of MPP+ and paraquat to target issues (brain, lung)
MPP+
+
drug metabolite
paraquat
chemical herbicide
+
+
putrescine
endobiotic
+
+
+
spermine
endobiotic
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Toxicant entry into the brain across the BBB
and toxic interactions with diverse cell types
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DA neuron uptake of MPP+ or agricultural toxicants
(rotenone, paraquat) affects mitochondrial ET chain
reactive oxygen species
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Metallic (elemental) mercury Hgo
is a liquid metal at room temperature
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Sources of exposure to mercury and methylmercury
in the environment
individual
exposures
community
exposures
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Movement of mercury in the environment and metal
speciation as Hgo, Hg2+ and methylmercury (MeHg)
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Mobilization from soil (or ice) and biomagnification of
mercury within the aquatic environment
chemical transformation
mobilization
atmospheric precipitation
biomagnification
in food chain
uptake by small
biota
wrong
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Organic mercury compounds: methylmercury (MeHg+),
ethylmercury (EtHg+), dimethylmercury, thiomersal
very lipophilic (supertoxic)
Methylmercury (MeHg)
(hydrophilic)
Ethylmercury (EtHg)
(hydrophilic)
very hydrophilic
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‘Molecular mimicry’: methylmercury (MeHg) mimics the
methyl sulfur group in the amino acid methionine
S
Pb
S
CH3Hg+ + Cys --> CH3Hg-S-Cys+
MeHg +
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cysteine --> cysteinyl methylmercury (~ mimics methionine)
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Transport of methylmercury (CH3Hg+) as a methionine mimic
across the BBB via the system L transporter (LAT1, LNAA)
luminal side (blood)
abluminal side (brain)
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Transport of methylmercury (MeHg) and possibly
ethylmercury (EtHg) across the BBB by LAT1 channel
MTF1 = metal regulatory transcription factor 1
LAT1 = large aminoacid transporter 1
MT1a = metallothionine
DMT1 = divalent metal transporter 1
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Exchange and sequestration reactions of methylmercury
within target cells (e.g. brain neurons)
uptake of MeHgSR molecules
via LAT1 transporter channel
(methionine mimicry)
sulfur-containing proteins (with cysteine residues) are molecular targets that
react by exchange with MeHgSR molecules (mercury exchange reactions)
selenium-containing proteins (with selenocysteine residues)
react irreversibly with MeHgSR molecules
(protective sequestration reactions)
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Mercury and lead and the risk of fetal toxicity
during early human development
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