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Department
Health
Course
HLTH 340
Professor
Steve Mc Coll
Semester
Fall

Description
Topic 4: Toxicokinetics - Absorption Part 2 and Heavy Metals Part 1 Toxicokinetics - Absorption Part 2 Factors Affecting Transport of Xenobiotics Across Membrane  Alright, so let's talk about passive diffusion (first). Which factors affect the RATE of passive diffusion? Expound on each. o Size of molecule: generally, if the MW (molecular weight) is < 200-500, it should be OK  On the other hand, bigger molecules penetrate to a lesser extent b/c their molecular weight and size is getting too big to squirt between the gaps (recall "paracellular" movement)  Sometimes even if a molecule is under 200-500 but it is CHARGED, it cannot pass through because:  It is charged (remember that the ionicity of the surface can repel it)  It attracts water molecules to become "solvated" and form a "sphere of hydration", and thus its size increases o Lipophilicity of xenobiotic (Ko/w > 1)  Of course, the more it exceeds 1 by, the greater the solubility in lipids o Concentration gradient: molecules naturally want to go from a high to a low concentration (to even out) and this is what provides the ENERGY for the molecules' movement -- if the concentration outside the cell is greater than inside, it will move inside spontaneously  A few things to note about concentration gradients:  In a static situation, soon enough we will get equal distribution of molecules on inside and outside and so you would think that concentration gradients cannot forever be the driving force behind transport  However, the reality in the BODY is that the blood removes the "in" part of the concentration through the circulation and so the gradient is always maintained  Also, sometimes a xenobiotic is GREATER on the blood side than on the EXTERNAL side -- and now the concentration gradient flows backwards -- this is "back diffusion" Example: drinking so much alcohol that you have lots of  it in your blood -- and this is why you can note alcohol on their breath  This happens because so much of the alcohol is in their bloodstream that it "back diffuses" (again due to concentration gradients) into the alveoli of the lungs, and then get breathed out o Membrane surface area: the more area it has available to cross, the more it will cross  The skin is only about 1 m2, so although absorption DOES happen here, it is not as much as, say…  …the GI tract, which is around 300 m2 thus lots of absorption can happen from the foods we eat  …and also finally the lungs, which are 100 m2 (again not surprising since it must have a big absorptive surface so as to take in oxygen Transcellular vs. Paracellular  Compare transcellular and paracelluar permeation. o Alright, so this is just describing how there are 2 ways to get through a membrane: you can go directly THROUGH the individual membrane cells (transcellular permeation) or you can try and squeeze between the cells (paracellular permeation) o Transcellular permeation: this is all that we have discussed so far -- either passive diffusion, facilitated diffusion, or active transport allows this to happen  Sometimes there are channels or carriers or pores or pumps to aid in this process (all of this we know) -- especially for hydrophiles  Also note that (as we know) this movement usually happens from the "apical" (external) to the "basolateral" (internal) side o Paracellular permeation: this is when we get across the membrane barrier by going around the individual cells  This is possible because while there are usually "tight junctions" between cells which "plug these holes", there are also places where it is quite a bit looser -- and so molecules can get in here Getting in Without Passive Diffusion  Explain what membrane transport channels are, and what they do. o Membrane transport channels are large glycoprotein molecules embedded in phospholipid membrane (also known as "membrane-spanning proteins")  "Glyco" means sugary -- thus there are sugar chains that project from the surface of the transporter protein out into the exterior space  The sugar branches act as a tag/label to tell outside guys about what this thing does o These guys act as channels (pores) that allow specific hydrophiles to cross membrane barriers  Note that this means they are SELECTIVE: they usually have a strong preference for a certain type of ion/molecule  They are usually differentiated based on size, shape, electrical charge (thus Na and K can use the same one -- we see later why this can be a problem) o There are other proteins associated with them that provide energy (check -- so they DO need ATP?)  Explain what active transport does. o This is something that increases rate of absorption because we intentionally use energy to pump molecules across the membrane (thus we do NOT rely simply on passive diffusion)  The energy source used is usually ATP o It can concentrate (or remove) substances in tissues (non-equilibrium) -- because it is able to move stuff AGAINST concentration gradients  Discuss facilitated diffusion. o This also increases the natural rate of absorption because it helps molecules to cross which would otherwise cross VERY SLOWLY (mostly because they are hydrophilic) o However, it does NOT work against a concentration gradient, thus it does not concentrate or eliminate substance in tissues (equilibrium)  Following from that, no energy source is required o Lastly, note that (as with active transport) it IS selective Absorption of Inorganic Ions Through Ion Transport Channels  Alright, so for these transport channels we've been talking about: we say they are selective (OK, fine). But HOW do they "select"? On what basis do they identify the "correct" molecules which should be allowed entry? o The answer is that size and ionic charge determines selective transport thru ion channels:  There are cation transport channels (K+, Na+, Ca++, etc.)  transport positively charged ions  monovalent (+1), divalent (+2), trivalent (+3), etc.  There are also anion transport channels (Cl-, I- , etc.)  transport negatively charged ions  monovalent (-1), divalent (-2), trivalent (-3), etc. o Notably, this is an imperfectly selective preference because it is not absolutely specific - and thus we can get TOXIC cations and anions which are allowed into the cell because they mimic the "healthy" ions which the channels are designed for  What are some factors which affect the rate of transport? o Affinity (high-affinity ==> rapid transport) o Saturation (rate-limiting factor for absorption speed) o Competition (2 substances compete for the same transporter channel) o Regulation (up-regulation or down-regulation by other factors) Example: Calcium and Lead  OK, first we'll talk about the calcium channel (later about lead). What do we know about it? o Well, it is an active transport pump that is used to absorb calcium from the intestine into the blood  Its specific name is "epithelial calcium channel type 2" (ECaC2)  It is also known as TRPV5 and TRPV6  As implied, it uses ATP o The uptake of calcium in this manner is regulated by Vitamin D, which tells a cell to produce more (or less) calcium channels  Vitamin D is made from sunlight, UV synthesis, melanization  This is why a Vitamin D deficiency disease (rickets) presents as bone malformation o Estrogen also encourages the development of these calcium channels  That is why old women can break bones easily (osteoporosis): they lose estrogen at menopause and thus they don't get enough calcium to build up their bones  Now talk about lead, and how it throws a wrench into this whole process. o Firstly, lead is everywhere in our environment so first let's establish that we are in no short supply of it  The real puzzlement is how it is able to enter our cells, seeing as it is big and charged - and we have said that cells usually reject these kinds of molecules o However, the thing is that lead is VERY SIMILAR to calcium -- a divalent cation, and so it can MIMIC calcium and go through the calcium channel o Lastly, we can use this information to do certain things to try and stop lead from poisoning us: if we take more calcium (i.e. calcium tablets), then all the calcium channels will be busy uptaking calcium and lead (since it is of lower affinity -- remember from above?) will lose out  If we were to look at a diagram of calcium transport from the GI lumen to the bloodstream, what would we notice? o We would see that processes OTHER that passive diffusion occur in multiple areas:  A calcium transporter is required to move the Ca2+ ions from the lumen through the apical membrane of the enterocyte and ultimately into the enterocyte (GI tract epithelial cell) (this is active transport, requires ATP)  A Ca/Na pump is required to move the calcium from the enterocyte through its basolateral membrane into the interstitial fluid separating the cell from the blood vessels (this is active transport, requires ATP) o We would see that passive diffusion occurs as well:  Once the calcium gets into the interstitial space, it can enter the bloodstream by going through FENESTRATIONS between the cells of the blood vessel o We see that Vitamin D affects this whole process by controlling the synthesis of the various calcium channels and transporters which are involved in the process o We notice that the free calcium concentration in the enterocyte is actually quite low -- this is because calcium is frequently bound to "calbindin" when it is in the cell  What would we notice when we looked at the structure of the TRPV6 (ECaC2) tetrameric calcium channel using molecular modeling? o We would see that the proteins are arranged in such a way that a calcium ion can perfectly fit in there and thus enter the cell o Note that this "opening" is 5.4 A Heavy Metals Part 1 Why Lead is Bad For You  Describe some of the environmental sources of lead. o Lead oxide (PbO) in leaded paints: they used to include lead in paint because when you oxidize it, it is a nice and bright WHITE color (also cheap)  However, when they paints dried out and cracked, all these flakes and dust would enter the environment and people would breathe it in  Also, sometimes young children would have "pica" (craving to eat unnatural articles such as rocks or dirt) and they would EAT the paint flakes because they tasted sweet -- but in doing so, they would get lead into themselves o Tetraethyl lead in gasoline: they used to include this in gasoline because it gave it a higher octane rating…but then as the gas was burned, the lead would enter the environment  So it came out into the environment and people breathed it  Also, this lead could enter the soils and dust in an area, and stay there as a continuous source of toxic pollution for a long time  Note that this is also possible in areas with not much automobile traffic, if instead there are things like lead smelters (i.e. Trail, BC) Talk about some of the neurological damage which lead can cause in children.  o Well firstly, it should be noted that small children in particular are at risk because their brains are enlarging: added cells are going into the brain, synaptic connections being established -- basis of learning, memory, cognitive skills, etc. o When it comes down to it, we see the consequences as:  IQ reduction and mild retardation  It is mild enough that it wouldn’t be a
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