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Topic 13.docx

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HLTH 340
Steve Mc Coll

Topic 13: Toxicodynamic Mechanisms - Enzyme Inhibition/Induction Nuclear receptor mediated toxicity - P450 enzyme induction by dioxins and PCBs  Quick reminder: what are some relevant properties of polyaromatic hydrocarbons? o They are products of incomplete combustion -- we are talking about methylcholanthrene and benzo-a-pyrene o Recall that they are hydrocarbon molecules made of multiple benzene rings  This means that they are: co-planar, lipophilic, unreactive o Although they are unreactive, remember that they are readily interact with P450 enzymes:  They can induce their synthesis (although the halogenated PAH's are even better at this)  They can also be metabolized by P450 enzymes and may be thus bioactivated: once they are bioactivated, many PAH compounds are genotoxic -- recall the lengthy discussion on BPDE  Since bioactivation is necessary we would refer to them as procarcinogens -- they are not inherently harmful but can be bioactivated to be so  Now let's discuss halogenated PAH's. Review the relevant elements of the chemical structure of the major types. o Alright, so often these guys will involve multiple benzene rings (usually 2) and the major variation is in how the benzene rings are attached:  There could be a dioxin in between, in which case we get stuff like tri- chloro-dibenzo-dioxin:  Also we could have a furan in between, which is similar to a dioxin with one less oxygen, in which case we get tetra-chloro-dibenzo-furan:  Or we could have no significant structure between the benzene rings, but just a C-C bond in which case we get stuff like tetrachlorobiphenyl: o Another significant aspect of the variations is that depending on what links the benzene rings together, they will either be coplanar (essentially flat) or not  When it is a single C-C bond between them, it is free to rotate and so the rings will not always be coplanar When we have a dioxin or a furan, it is not free to rotate and so the rings  are coplanar  Explain the concept of congeners, and what their relevance is to this discussion. Discuss one congener which is particularly gangster. o "Congeners" refer to isomers of a molecule which have the same core structure but differ in a) number of substituents and b) location of substituents o Obviously they are relevant to our discussion of HPAH's because HPAH's are characterized by having halogen substituents -- and so we see that something like dioxin (for example) in fact refers to a GROUP of HPAH's which share a dioxin element in the middle but differ in the number and location of substituents o Also notable is that of all the different dioxins (recall that they are one of THREE HPAH's that we discussed), 2,3,7,8-TCDD is the worst congener because of the number of chlorines it has, and the location of them  It is toxic to many different regulatory systems in the body i.e. liver, reproductive organs, skin, lungs -- it is the most toxic of all manmade toxins  Discuss the consequences to human health of the different HPAH's. o Well in general, they are all pretty bad:  HPAH's often resist Phase-1 metabolism by P450 enzymes (recall that they induce Phase 1 enzyme production but the Phase 1's cannot actually break them down because all the halogens act as blocking groups  In addition, many HPAH are endocrine disruptor chemicals (EDC's) -- they mimic hormones or other regulatory stuff like growth factors  These include cortisone, estrogen, testosterone, thyroid hormone, etc. o In particular, we notice that dioxins and furans are worse than the polychlorinated biphenyls -- some suggest that this is due to the fact that dioxins and furans are coplanar (as previously discussed) while PCB's are not, but we will leave the justification for that to another discussion  However we do have proof: although pcb have similar effect to dioxins and furans, they do so with less potency -- it takes larger quantities of pcb's (milligram quantities) to do the same level of toxicity as compared to dioxins and furans (microgram quantities)  So we have established that PCB's are not as bad as dioxins and furans. Comment on the prevalence of PCB's in the environment to justify why this fact comes as a relief to us. o Basically, we are happy to hear this because PCB's are still everywhere in the environment: from 1920 to 1980 we made millions of tons of it, and since they are resistant to biodegradation and are persistent in the environment, they are still around o For example: A lot of times we used pcb as cooling fluids in the transformers for older  buildings, and they become especially hazardous if there is a fire because pcb's could vaporize  And when that happens, they break down and make dibenzofurans and dibenzodioxins which are WAY MORE TOXIC  Pcb's are also found in waste dumps -- -chemical waste dumps, etc….basically any electrical equipment before 1980 will probably have pcb oil in the condenser, transformer, etc.  Also consider the use of pcb's in the canadian arctic (?): we were always scared that russians would come over the north pole with bombers, and so we built radar stations -- distant early warning systems  And radar takes up a lot of power and so we had a huge generator that was full of pcb's and every so often we have to service/replenish them so we bring up huge tanks of pcb's  But at the end of the cold war they just left the stations and didn't touch the pcb's and so now we have all these radar stations that are leaking…have tons of poorly stored quantities of pcb's Dioxins, furans, and other HPAHs are endocrine disrupting chemicals (EDCs)  Give a high level overview of the consequences to us from dioxins. o We firstly note that dioxins can produce pleiotropic effects on regulatory processes (i.e. many different results/consequences)  That is, many different cellular hormone systems are altered or modulated o In particular, some dioxins or dioxin-like compounds (see later) show anti- estrogenic effects -- i.e. exposure to dioxins causes the effects normally facilitated by estrogen to decrease o Notably, dioxides, furans, and PCB's all do the same kinds of things and so we often refer to all of them as "dioxin-like compounds"  Let's hone in on estrogen a bit. Explain where we have been in terms of thinking about how these "anti-estrogen" effects are caused. o Well firstly, we thought that TCDD (let this be our dioxin for now) would be similar to Tamoxifen (a breast cancer drug), which works by blocking estrogen receptors on cancerous breast cells such that it cannot receive estrogen (which causes it to grow)  Interesting notes on tamoxifen:  It is sometimes used as a chemopreventive drug, but probably best to use it only in people who have a high risk for BC (i.e. not everyone) o However, we noted that TCDD is not a ligand for ER or other sex hormone receptors -- that is, dioxins are NOT estrogen receptor blockers o So we continued on from there…and ultimately we found that TCDD stops estrogen signaling at the nuclear level -- doesn't block the binding of estrogen at the receptor but instead it interferes with the signals that the receptor tries to send to the cell nucleus (ummm what?)  Alright, so if it doesn't act like Tamoxifen, then explain how it works. o In a sentence: it alters estrogen degradation pathways via CYP 1A1/1A2 induction Remember how 1A1/1A2 not only breaks down xenobiotics but also  steroid hormones? Well it turns out that estrogen is one of these, and so if we are able to control the level of 1A1/1A2, then it means that we can control how quickly or slowly estrogen is broken down and made unusable o The deal is that there is an Ah-receptor (NSAhRM?) system within the cell that acts like a response element (just like Keap/Nrf from before), and TCDD induces this and it sets off a chain reaction that results in more 1A1/1A2 guys being synthesized  Discuss these "response elements" further and explain the role they play in the tug of war between estrogen and dioxins. o Remember that a response element is just some sort of system that can respond to a signal (i.e. entry of dioxin or estrogen) and RESPOND by affecting the rate of transcription of some gene (for example) o So we have already discussed how dioxin -> Ah -> CYP 1A1/1A2 works: and this is an example of an inhibitory dioxin response element (iDRE), because activating it causes something to be inhibited o However it turns out that there are also ERE (estrogen response elements), which are activated by estrogen and cause the transcription of genes such as c-fos, which are necessary for cell division  This is why we say that estrogen can cause cell growth o And so there is a battle between the iDRE's and ERE's because they oppose each other -- and the winner is going to be the one who is induced the most by either dioxin or estrogen, respectively  What is the big picture? o The big picture is that TCDD can modulate/reduce the risk of breast cancer because it will inhibit estrogen's effect and thus retard cell growth Dioxin contamination of 2,4,5-T herbicide (Agent Orange) in Vietnam war (1964-73)  Give a quick description of the history behind Agent Orange, that led eventually to the discovery of dioxin. o The US was at war with Vietnam, and they found it difficult to deal with the guerrillas because of the dense forest which they could hide in, being their natural habitat and all o So they decided to spray tens of thousands of tons of herbicide over a large part of Vietnam, which was intended to defoliate the trees so that the army could see better o The principal component of the herbicide was 2,4,5-T herbicide, which was supposed to be safe for humans o So they sprayed tons of it onto Vietnam's land, and after a few years the villagers in those areas started to notice abnormalities (more later) o The 2,4,5-T spray was studied and it was discovered that a foreign and unexpected element -- codenamed "Agent Orange" -- was in the spray o It turns out that this element was dioxin, and that it had been accidentally created as a byproduct when Dow Chemical (an American chemical company) was manufacturing the 2,4,5-T  What were some of the clinical indications of TCDD for the villagers who were exposed to it? o The big picture is that TCDD is a potent teratogenic agent, which means that it will cause birth defects by interfering with regulatory control of the CNS and head development in the embryo. These include:  Anencephaly (born with no brain inside the skull)  Cleft palate (oral deformity)  Spinal bifida (incomplete closure of the neural tube) o Also, it was suspected to disrupt the retinoid hormone systems (Vitamin A)  Also talk about its chronic effects for adults, specifically in the liver and lung. Explain the mechanism. o Well as we may recall, it is a super-inducer of P450 1A1 /1A2 enzymes -- meaning that it causes increased enzyme synthesis but is itself NOT broken down by these enzymes because of the halogen blocking groups o This results in excessive MFO activity, with the (liver) cells becoming overloaded with smooth ER and the enzymes -- this leads to metabolic imbalance and cell death o We see this especially in the liver and lung, because 1A1 and 1A2 go there a lot  Now discuss TCDD's potency as an endocrine disruting chemical (EDC). o The main mechanism by which it disrupts the hormone system is through its anti- estrogen effects: causing an excessive rate of estrogen degradation o This works because of how it induces 1A1 and 1A2 production, which by chance are also responsible for the degradation of estrogen o Thus the increased 1A1/1A2 levels will result in excessive estrogen degradation and the ovaries and breasts (especially) are damaged  Lastly, explain how TCDD can act as a carcinogen. Explain how it is a unique carcinogen. o Well firstly, it is unique because unlike most other carcinogens, it does not cause MUTATIONS -- it is a non-genotoxic carcinogen. o Instead, it is an epigenetic carcinogen, meaning that it exerts its effects by controlling the expression of genes (more later)  Discuss the effect that the AMOUNT of TCDD exposure can have on this discussion. o Usually we say that more of it is needed to cause cancer than to cause some of the other consequences, such as reproductive effects o The effect on reproduction is worsened because now it affects truly productive members of the population -- it is not just the older people who get cancer, but also young women carrying babies who are greatly affected o Also relevant to this discussion is that TCDD is VERY P, B, and T: its half life is 10 years  Lastly, discuss some of the ways that the Vietnamese were exposed. o Also airborne contamination is an issue -- i.e. aerial spraying of chemicals, pesticides, etc…or on the skin from brushing against vegetation or getting soil on your skin that has been contaminated o So although most of the time we worry about the food sources, we might also want to think about the exposures that are airborne or in vegetation and soil Attempted assassination by dioxin poisoning President Victor Yushchencko (Ukraine)  Briefly explain the circumstances surrounding the dioxin poisoning of Victor Yushchencko. o It was a political thing: he led the anti-Russian party and the pro-Russian party poisoned him o As one might expect with dioxin, there were no immediate effects (it's not an acute agent) but eventually he also started to get stuff like chloroacne (oily skin,
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