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Topic 15.docx

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HLTH 340
Steve Mc Coll

Topic 15: Toxicodynamic Mechanisms - Free-Radical Toxicity Part II Sources of free radicals and oxidative stress  Again, what are some endogenous and exogenous sources of free radicals? Expound where necessary. o exogenous radicals  environmental oxidants (O3, NO2)  metabolic activation of xenobiotics  ionizing radiation  phagocytosis and inflammatory immune processes  free radical sensitizers -- i.e. free radical producers o endogenous radicals: many of these are generated within the cell through 1- electron transfer, which is when electrons enter biological reactions which they are not supposed to enter, and a single electron gets transferred  For example this can happen in:  Mitochondria: ET chain for oxidative phosphorylation (ATP production)  microsomes (smooth E.R.): ET chain for oxidative P450 reactions  Lysosomes: oxidative burst in phagocytosis (‘killing action’)  cell membrane: synthesis of inflammatory mediators (e.g. prostaglandin synthetases) Production of superoxide radical by 1-electron rxn at complex II in the mitochondrial ET chain  So let's look into an example of how an accidental one-electron transfer can happen. Give a BRIEF overview of the ET (electron transfer) chain, and explain how an accidental one-electron transfer can occur. o Well recall that the electron chain is just the process of passing electrons to different complexes which want those electrons more and more -- and so as we pass the electron to something that wants it badly, it goes to a lower energy state and we can use the released energy to pump protons across o Sometimes we use shuttles to move the electrons from one complex to another:  Cytochrome C is the shuttle from 3 to 4  Coenzyme-Q is the shuttle between 1 and 3 o The point is that Co-Q is unfortunately accident prone/sloppy  Sometimes (1% or less), it will accidentally create a ONE-electron transfer (YIKES!) -- this gives the opportunity to have a superoxide, which you recall is O 2 o And thus we say that this is the leaky part of electron transfer Oxygen toxicity  What is the big picture here? What are the two types of oxygen toxicity we are discussing? o Oxygen toxicity is the idea that having too much OXYGEN can be toxic -- i.e. damaging to the body o The two types of oxygen toxicity we will explore are:  Pro-oxidants (i.e. nitrite), and what they can cause with oxygen and heme  Oxygen toxicity from hyperbaric/100% oxygen  First explain what the deal is with oxygen and heme. o Well firstly, recall that the heme group on hemoglobin (Hb) molecule is supposed to carry oxygen around -- so it'll bind to oxygen, bring it somewhere, then let it go (normally to myoglobin, but that is a separate discussion) o The deal here though is that the oxygen will steal an electron from the heme and become a superoxide radical! Not good! o Thus the progression we see is reduced hemoglobin aka hemoglobin (Fe++) -> oxygenated hemoglobin aka oxyhemoglobin (Fe++ -- O2) -> oxidized hemoglobin aka methemoglobin (Fe+++) o And the thing is that high levels of the pro-oxidant nitrite will drive this reaction forward, and so it is dangerous  It results in methemoglobin anemia, which is not enough oxygen due to the formation of methemoglobin  Kids will turn blue/purplish =/  Explain what the deal is with 100% oxygen/hyperbaric oxygen. o The mechanism is simplistic:  Higher levels of oxygen result in the greater production of superoxide radicals  These guys in turn can damage the:  Lungs, leading to bronchopulmonary dysplasia  Retina, leading to retrolental fibroplasia o Notably, large doses of vitamin E can rapidly reduce retrolental fibroplasia and bronchopulmonary dysplasia because it neutralizes the superoxides  Explain the contextual issues surrounding this. o Often it is NECESSARY to give such high doses of oxygen: for example when a baby is premature  So we give it to them to save their lives, but it can cause tissue damage as a result P-450 production of ROS and radical metabolites (bioactivation of xeniobiotics)  What was the point of this slide?
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