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Free radical = a solitary electron in a shell on an atom, looking for a partner. Very reactive, and can steal partners from other atoms and injure cells.

A few types of free radicals include:
superoxide (O2-)
nitric oxide (NO)
hydrogen peroxide (H2O2)
hydroxyl radicals (OH- =baddie, most reactive, generated by chlorox, HOCl)
organic radicals (R-)
organic peroxide radicals (RCOO-)
hypochlorous acid (HOCl)
singlet oxygen, (O2 with antiparallel spins that is produced at high oxygen tensions frmo the absorbtion of energy, and decays with the release of light)

The Fenton reaction: Fe2+ + H2O2 --> Fe3+ + 2OH-. This is the big generator of ROS in biological systems. Used commercially as Fenton's reagent to oxidize contaminants or waste waters, destroy organic compounds such as trichloroethylene (TCE) and tetrachloroethylene (PCE).

Why is the Fenton Rxn important? Ie, why do we do this even though it produces ROS? There is lots of iron in the body, and the mismanagement of iron in cellular systems can lead to the toxic accumulation of iron in organ systems such as the liver and brain (hemochromatosis). It is believed that this build up of iron eventually leads to the production of free radicals leading to oxidative stress, cellular damage and eventual cellular death via apoptotic signaling.

UNANSWERED: How do we process the Fe3+ form of iron? How is that different from what happens with the Fe2+ form?

What else generates free radicals in the body?
ENDOGENOUS
1) enzyme activity
2) eletron transport chain (CoQ10)
3) phagocytic respirtory burst
EXOGENOUS
4) UV light
5) drugs
6) air pollution.

What immune cells produce ROS (reactive oxygen species) and for what purpose? White blood cells, specifically neutrophils (a type of granulocyte), use H2O2 and lysozyme to kill bacteria after they have swallowed them.

DRINKING AND SMOKING KILL YOU VIA FREE RADICALS
What kinds of damage can free radicals do in cells? Athlerosclerosis, Parkinson's disease, MS, kidneys, aging, senile and drug-induced deafness, schizophrenia, Alzheimer's, contribute to alcohol-induced liver damage, perhaps more than ALCOHOL itself. Radicals in cigarette SMOKE have been implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema.

Xenobiotics = foreign substances

Phase I Detox System
--hydroxylation reactions
--cytochrome p450's (CYPs) = mono-oxygenases = add oxygen to carbon chain
--14 families of CYP, more subfamilies
--CYPs contain heme group, red color
--highest # of CYPs in liver, also in lungs, small intestine
--in endoplasmis reticulum (ER) and some in mitochondria
--wide range of substrate specificities
--most CYPs are inducible, meaning they are not always expressed
--some CYPs exist as polymorphs, variation in enzyme activity can be found among individuals, hence variable responses to drugs & herbs
--called the cytochrome P450 enzyme system
--liver uses oxidation, reduction, hydrolysis or hydroxylation to disarm baddies
--during this process oxygen free radicals are generated, so there is a need for antioxidants, especially Vitamin C, to prevent cellular damage
--liver NEEDS: selenium, folic acid, B2, B3, B6, phophatidyl choline, bioflavonoids
-- Fast foods and processed foods are deficient in liver nutrients
--overeaters who eat junk can still be terribly deficient in these nutrients

Phase II Detox System
--conjugation reactions
--render xenobiotics more water soluble
--lead to excretion via urine or bile
--six types: 1. glutathionation, glucuronidation, acetylation, add aa, sulfatoin, methylation.
--glucuronidation is the MAJOR one, broad range of substrates, UDP glucose can make glycogen or glucaronic acid for this, adds to acetomenophen, bilirubin
--called the conjugation pathway
--liver cells add either a glycine or sulphate molecule to a chemical to make it water soluble so it can be excreted from the body via fluids such as urine or bile
--liver NEEDS: Vitamin E, carotene, sulphur containing amino acids (taurine, methionine, cysteine), glycine, glutamine, choline and inositol
--Best FOODS: Cruciferous vegetables (cabbage, cauliflower, broccoli, brussel sprouts) are a good source of natural sulphur compounds for the liver (cilantro and garlic too!!!)

MORE DETOX FACTOIDS
--body can do phase I or phase II or both in order
--some toxins can be detoxed in a variety of ways, for example salicylic acid (aspirin) can be aceylated, glucuronidated or conjugated.
--if one or both detox pathways are overloaded, there is a build up of toxins
--many toxins are fat soluble and stay in fatty cell membranes for YEARS
--pesticides, petrochemicals, aspartame are toxic to nervous sys and endocrine, also carcinogenic
--inefficient detox --> harmful substances and micro-organisms build up in the blood
--immune system --> overloaded and hyperstimulated
--examples: allergies, inflammatory states, recurrent infections, swollen glands, chronic fatigue or auto-immune disease

What tissues are most important in detox rxns? liver liver liver, to a lesser degree lungs, small intestine, skin.

How can detox system backfire?
--sometimes CYPs make something more dangerous, ex: benz[a]pyrene, coal tar anthracine
--responses to xenobiotics may be pharmacologic (codeine to morphine), toxic, immunologic or carcinogenic
--drug interactions: the same CYP works on cumidin or warfarin for blood clotting and some siezure med so inducement of that CYP of one med may increase the needed dose of the second
--age & gender affects detox enzymes (dosing matters)
--food: BRUSSEL SPROUTS induce a CYP that processes codeine and also reduces the conversion of testosterone to estradiol

What are three anti-oxidant enzymes and their substrates, what metals are components of these, and where are they located in the cell?

GLUTATHIONE PEROXIDASE
substrate: H202 --> H2O and lipid hydroperoxides --> alcohols
metal: selenium
location: mitochondrial matrix

CATALASE
substrate: H2O2 --> H2O + O2
metal: iron
location: in peroxisomes where we catabolize long fatty acids using H2O2
other:
--most found in Root vegetables such as Potatoes and Celeriac
--super high turnover rate
--tetramer of four polypeptide chains
--contains four porphyrin heme (iron) groups
--optimum pH for catalase is approximately (pH 7.0)
--optimum temperature varies by species.[5]

SUPEROXIDE DISMUTASE = SOD
substrate: O2- --> O2 and H2O2
metals: Cu, Mn, Fe, Ni
location: in cytosol and matrix of mitochondria

ANTIOXIDANTS
Discuss the relationship of vitamin E, vitamin C, glutathione peroxidase as antioxidants. What is the cellular locations of these antioxidants?

Vitamin E
--terminates free radical perioxidation by donating single electrons to form the stable, fully oxidized tocophyeryl quinone, which has an aromatic ring.
--alpha-tocopherol is the only one of 8+ tocopherols that is put into VLDL's, this is the name for the active form, is the most common in the diet
--alpha-tocopherol has a long lipid tail that inserts into membranes, is made of isoprene units
--tocotrienols have same head as alpha-toco but tails have double bonds (hence triene).
--tocotrienols have 25% the antioxidant capacity of alpha tocopherol
--other reactions that are simliar to what vitamin E does: quinol <-->quinone, CoQ10 and Vitamin K.

Vitamin C
--helps with the reduction (recharging) of Vitamin E.
--where is vitamin C found in the body? everywhere????
--aka. L-ascorbate is an essential nutrient for higher primates, and a few others
--important for almost all organisms
--made internally by almost all organisms, humans being one notable exception
--deficiency causes scurvy in humans
--widely used as a food additive.
--the pharmacophore of vitamin C is the ascorbate ion.
--In living organisms, ascorbate is an antioxidant, as it protects the body against oxidative stress
--ascorbate is a cofactor in several vital enzymatic reactions.
--BIOSYNTHESIS BY OTHER SPECIES: the vast majority of animals and plants are able to synthesize their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C. The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.In reptiles and birds the biosynthesis is carried out in the kidneys. An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "many fold under stress". Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.
--OTHER SP THAT DON'T BIOSYNTHESIZE: Among the animals that have lost the ability to synthesise vitamin C are simians, guinea pigs, the red-vented bulbul, and fruit-eating bats. The last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene for enzyme: Pseudogene ΨGULO is defective. The mutation has not been lethal because vitamin C is abundant in their food sources, with many of these species' natural diets consisting largely of fruit.
--DOSING NOTEs: Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans. This discrepancy constitutes the basis of the controversy on current recommended dietary allowances.
--Trauma or injury has also been demonstrated to use up large quantities of vitamin C in humans.
--EVOLUTIONARY NOTE: The loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that in higher primates, uric acid has taken over some of the functions of ascorbate. Ascorbic acid can be oxidised (broken down) in the human body by the enzyme ascorbic acid oxidase.
--All this circles me back around in my mind to learning that Helicobacter pylori, which is given in modern medicine as the major cause of gastric ulcers, is inhibited by vitamin C. So here we are, evolved from the apes that ate little but fruit, now eating pizza instead of berries.

Glutathione peroxidase is in the mitochondrial membrane per Bracey, wikipedia says it's in most mammalian cytoplasm but is crucial for the maintanance of cell and subcellular membranes. Glutathione peroxidase (PDB 1GP1, EC 1.11.1.9) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.
--REDUCEs LIPID HYDROPEROXIDES TO ALCOHOLS, H2O2 TO H20
--1st line of defense against ROS, along with other antixidant enzymes: SOD & catalase
--must have SELENIUM for this enzyme
--several isozymes encoded by different genes, which vary in celullar location and substrate specificity
--most abundant isozyme: Glutathione peroxidase 1, found in most mammalian cytoplasm, substrate is hydrogen peroxide
--Glutathione peroxidase is a selenium-containing tetrameric glycoprotein
--the integrity of cellular and subcellular membranes depends heavily on glutathione peroxidase, the antioxidative protective system of glutathione peroxidase itself depends heavily on the presence of selenium.

What is the role of the pentose pathway in maintaining red blood cell integrity?
--Key enzyme is: glucose-6-phosphate dehydrogenase, in the oxidative portion of the pathway
--erythrocytes require NADPH to keep glutathione reduced to maintain membrane
--erythrocytes have no other source of NADPH besides the pentose pathway
--glutatione is our 1st line of defense for membranes against ROS (also SOD & catalase)
--if no NADPH then hydrogenperoxide levels increase and membranes get lysed

NADPH
--The oxidative phase of the pentose phosphate pathway is the major source of NADPH in cells.
--Nicotinamide adenine dinucleotide phosphate (NADP+, in older notation TPN) is used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent.
--NADPH is the reduced form of NADP+, and NADP+ is the oxidized form of NADPH.
--In PLANTS in chloroplasts, NADP is reduced by ferredoxin-NADP+ reductase in last step of the electron chain of the light reactions of photosynthesis. The NADPH produced is then used as reducing power for the biosynthetic reactions in the Calvin cycle of photosynthesis.
NADP ions in photosynthesis may be seen as 'dragging' hydrogen ions along with them (in the light-dependent cycles), which are used by the light-independent (Calvin) cycles to produce carbohydrates.
--provides the reducing equivalents for biosynthetic reactions and for oxidation-reduction involved in protection against the toxicity of ROS (reactive oxygen species).
--used for anabolic pathways, such as lipid synthesis, cholesterol synthesis and fatty acid chain elongation.
--source of reducing equivalents for cytochrome 450 hydroxylation of aromatic compounds, steroids, alcohols, and drugs.

HEMOCHROMATOSIS
Hemochromatosis is typically-associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentary melanin abnormalities, deafness, arthritis, and diabetes mellitus.

Respiratory burst
--AKA oxidative burst
--=rapid release of reactive oxygen species (superoxide radical and hydrogen peroxide)
--usu from immune cells, (neutrophils and macrophages) trying to kill bacteria or fungi
--also released from the ovum of higher animals after the ovum has been fertilized (stopping double fertilization!!! is this triggered by that stuff in the tip of the sperm???)
--can also be released from plant cells
--crucial reaction in phagocytes to degrade internalized particles and bacteria
--NADPH oxidase, an enzyme family in the vasculature (particularly in vascular disease), produces superoxide, which spontaneously recombines with other molecules to produce reactive free radicals. The superoxide reacts with NO, resulting in the formation of peroxynitrite, reducing the bioactive NO needed to DILATE TERMINAL ARTERIOLES, feed arteries and resistance arteries.
--Superoxide anion, peroxynitrite, and other reactive oxygen species also lead to pathology via peroxidation of proteins and lipids, and via activation of redox sensitive signaling cascades and protein nitrosylation.
--Many vascular stimuli, including all those known to lead to INSULIN resistance, activate NADPH oxidase via both increased gene expression and complex activation mechanisms.

FREE RADICAL FACTOIDS:
-- = atomic or molecular species with unpaired electrons on otherwise open shell config.
--unpaired electrons are usually highly reactive
--superoxide and nitric oxide regulate many biological processes, such as controlling vascular tone.
--MITOHOMESIS theory ???--opposite of free radical theory, this theory proposes that repeated exposure to free radicals may extend life span. based on what???
--functional groups are attached in some molecules, hold e- and remain unchanged
--Most familiar free-radical RXN: combustion.
--oxygen molecule is a stable diradical, best represented by ·O-O·, which is stable because the spins of the electrons are parallel. The ground state of oxygen is an unreactive spin-paired (triplet) radical, but an extremely reactive spin-unpaired (singlet) radical is available.
--When a hydrocarbon is burned, a large number of different oxygen radicals are involved. The first thing to form is a hydroperoxide radical (HOO·), which reacts further into hydroperoxides that break up into hydroxide radicals.
--In order for combustion to occur, the energy barrier between these must be overcome. This barrier can be overcome by heat, requiring high temperatures, or can be lowered by enzymes to initiate reactions at the temperatures inside living things.
--Combustion is comprised of various radical chain reactions that the singlet radical can initiate. The flammability of a given material is strongly dependent on the concentration of free radicals that must be obtained before initiation and propagation reactions dominate leading to combustion of the material. Once the combustible material has been consumed, termination reactions again dominate and the flame dies out. Propagation or termination reactions can be promoted to alter flammability. Tetraethyl lead was once commonly added to gasoline, because LEAD itself deactivates free radicals in the gasoline-air mixture. This prevents the combustion from initiating in an uncontrolled manner or in unburnt residues (engine knocking) or premature ignition (preignition).

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