HLTH 340 Lecture A5 Toxicokinetic processes: Distribution (part-2) internal membrane barriers NOTICE: These materials are subject to Canadian copyright and are presented here as images published in journals and books for which the University of Waterloo holds a licensed electronic subscription. These materials are provided to HLTH 340 students for their exclusive use though a non-public courseware system (UW-LEARN) and the images are restricted to the use of HLTH 340 students. Reproduction, transmittal, copying, or posting of these images by students in any form, electronic or physical, is strictly prohibited.

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)

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

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

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

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

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

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

‘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

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

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

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

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

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

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

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

‘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)

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

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

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)

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