1. HLTH 340 Lecture A5 Toxicokinetic processes: Distribution (part-2)
internal membrane barriers
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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)

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

4. The blood-brain barrier (BBB) prevents/restricts the flow of xenobiotics and drugs from the blood to the brain tissue

5. Tight junctions in the capillary endothelium prevent paracellular permeation across the blood-brain barrier

6. P-glycoprotein (P-gp) and related MDR / MRP efflux pumps expel many xenobiotics at the blood-brain barrier

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 Parkinson’s disease

8. Redox trapping (ion trapping) of MPTP / MPP+ at the BBB via MAO-B oxidation

9. ‘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

10. Toxicant entry into the brain across the BBB and toxic interactions with diverse cell types

11. DA neuron uptake of MPP+ or agricultural toxicants (rotenone, paraquat) affects mitochondrial ET chain
reactive oxygen species

12. Metallic (elemental) mercury Hgo is a liquid metal at room temperature

13. Sources of exposure to mercury and methylmercury in the environment
individual
exposures
community
exposures

14. Movement of mercury in the environment and metal speciation as Hgo, Hg2+ and methylmercury (MeHg)14

15. 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 15

16. Methylmercury (MeHg) (hydrophilic) Ethylmercury (EtHg) (hydrophilic)
Organic mercury compounds: methylmercury (MeHg+), ethylmercury (EtHg+), dimethylmercury, thiomersal
very lipophilic (supertoxic)
Methylmercury (MeHg) (hydrophilic)
Ethylmercury (EtHg) (hydrophilic)
very hydrophilic 16

17. ‘Molecular mimicry’: methylmercury (MeHg) mimics the methyl sulfur group in the amino acid methionine S S Pb
CH3Hg+ + Cys --> CH3Hg-S-Cys+
MeHg cysteine --> cysteinyl methylmercury (~ mimics methionine)

18. Transport of methylmercury (CH3Hg+) as a methionine mimic across the BBB via the system L transporter (LAT1, LNAA)
luminal side (blood)
abluminal side (brain)

19. 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

20. 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)

21. Mercury and lead and the risk of fetal toxicity during early human development