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Slide 1 - 1 What is an antioxidant? How do antioxidants work? Garry R. Buettner and Freya Q. Schafer Free Radical and Radiation Biology Program and ESR Facility The University of Iowa Iowa City, IA 52242-1101 Tel: 319-335-6749 Email: garry-buettner@uiowa.edu or freya-schafer@uiowa.edu SFRBM Sunrise Free Radical School
Slide 2 - 2 Antioxidants, the road ahead Overview and vocabulary Preventive Chain-breaking Retarder vs true antioxidant This presentation focuses on the action/reaction of small molecule antioxidants.
Slide 3 - 3 Antioxidants: A definition A substance when present in trace (small) amounts inhibits oxidation of the bulk. OR A little bit goes a long way. So, what is a little bit?
Slide 4 - 4 Antioxidants: two broad classes Preventive and Chain-Breaking Preventive antioxidants intercept oxidizing species before damage can be done. Chain breaking antioxidants slow or stop oxidative processes after they begin, by intercepting the chain-carrying radicals.
Slide 5 - 5 Elementary Lipid Peroxidation L-H + X ¾® L + XH Initiation 3 x 108 M-1 s-1 L + O2 ¾¾¾¾® LOO Propagation  40 M-1 s-1 LOO + L-H ¾¾¾¾¾® L + LOOH Cycle LOO + “R” ¾¾¾¾¾® LOOR Termination
Slide 6 - 6 Preventive Antioxidants Don’t let it get started.
Slide 7 - 7 Preventive antioxidants act by: Deactivating metals, e.g. transferrin, ferritin, Desferal, DETAPAC, EDTA, … Removing hydroperoxides, e.g. catalase, glutathione peroxidases, pyruvate, … C. Quenching singlet oxygen, e.g. -carotene, lycopene, bilirubin, …
Slide 8 - 8 Preventive Antioxidants: Targeting Metals Fe & Cu are the principal metals targeted– loosely bound*   Proteins & metals – Transferrin / Hemoglobin / Ceruloplasmin Chelates – Fe3+ – EDTA, DETAPAC (DTPA), Desferal Fe2+ – Phenanthrolines, … * “Loosely” bound iron on proteins, DNA as well as iron in hemes can be dangerous.
Slide 9 - 9 Preventive Antioxidants: Why target metals? Because they promote oxidant production.   Fe(II)chelate + H2O2  HO + Fe(III)chelate + OH- or Fe(II)chelate + LOOH  LO + Fe(III)chelate + LOH and Fe(II)chelate + O2  Oxidantsa a Qian SY, Buettner GR. (1999) Iron and dioxygen chemistry is an important route to initiation of biological free radical oxidations: An electron paramagnetic resonance spin trapping study.Free Radic Biol Med, 26: 1447-1456.
Slide 10 - 10 Metal Deactivation Fe(III)/Fe(II) EDTA E = + 120 mV Rxn with O2- k = 106 M-1 s-1 DETAPAC E = + 30 mV Rxn with O2- k < 102 M-1 s-1
Slide 11 - 11 Metal Deactivation: Why the difference? Fe(III)EDTA Size -- too small, leaving a site for H2O H2O
Slide 12 - 12 Metal Deactivation: Desferal E (Fe(III)DFO/Fe(II)DFO) = - 450 mV Kstability Fe(III)  1030.6 k (with O2-) < 103 M-1 s-1 Kstability Fe(II)  107.2 De-activates Fe(III) kinetically (no H2O of coordination) and thermodynamically.
Slide 13 - 13 Preventive antioxidants act by: Deactivating metals, e.g. transferrin, ferritin, Desferal, DETAPAC, EDTA, … Removing hydroperoxides, e.g. catalase, glutathione peroxidases, pyruvate, … C. Quenching singlet oxygen, e.g. -carotene, lycopene, bilirubin, …
Slide 14 - 14 Enzymes targeting peroxides: H2O2 , LOOH Catalase: 2H2O2  2H2O + O2 GPx (GPx1): H2O2 + 2GSH  2H2O + GSSG or ROOH + 2GSH  H2O + ROH + GSSG PhGPx (GPx4): PLOOH + 2GSH  PLOH + GSSG + H2O Prx (peroxidredoxins): H2O2 + Trx(SH)2  2H2O + Trx(SS) 1-cysPrx: PLOOH + 2GSH  PLOH + GSSG + H2O Non-enzymatic rxns H2O2 + 2GSH  2H2O + GSSG or ROOH + 2GSH  H2O + ROH + GSSG
Slide 15 - 15 Glutathione (GSH) Glutathione is a tri-peptide
Slide 16 - 16 Preventive Antioxidants: Removing Hydroperoxides  GSH will react directly with H2O2, albeit very slowly. 2 GSH + H2O2  2 H2O + GSSG kobs (7.4)  1 M-1 s-1 * Appears to be too slow for biological significance. * Estimated from: Radi et al. (1991) J Biol Chem. 266:4244-4250.
Slide 17 - 17 Hydroperoxide removal by GSH is mainly via coupled enzyme reactions 2 GSH + ROOH  GSSG + H2O + ROH
Slide 18 - 18 Pyruvate and H2O2 Pyruvate is a three-carbon ketoacid produced during glycolysis. Pyruvate can remove H2O2 by a stoichiometric chemical reaction. Pyruvate Acetate
Slide 19 - 19 Preventive antioxidants act by: Deactivating metals, e.g. transferrin, ferritin, Desferal, DETAPAC, EDTA, … Removing hydroperoxides, e.g. catalase, glutathione peroxidases, pyruvate, … C. Quenching singlet oxygen, e.g. -carotene, lycopene, bilirubin, …
Slide 20 - 20 Singlet oxygen quenching, avoiding peroxides Singlet Oxygen 1O2, i.e. oxygen with extra energy 1gO2 23.4 kcal mol-1 above the ground state Singlet oxygen is electrophilic, thus it reacts with the double bonds of lipids. (No free radicals; hydroperoxides formed.) k  2 x 105 M-1 s-1 1O2 + PUFA  PUFA-OOH
Slide 21 - 21 LOOHs: 1O2 vs radicals
Slide 22 - 22 Quenching of 1O2 1O2 + -carotene  O2 + -carotene* -carotene*  -carotene + heat Chemical quenching is a term used to signify that an actual chemical reaction has occurred. Hydroperoxide formation is chemical quenching. 1O2 + LH  LOOH Physical quenching is the removal of the excitation energy from 1O2 without any chemical changes.
Slide 23 - 23 Antioxidants, the road ahead Overview and vocabulary Preventive Chain-breaking Retarder vs true antioxidant
Slide 24 - 24 Chain-Breaking Antioxidants In general chain breaking antioxidants act by reacting with peroxyl radicals, ROO
Slide 25 - 25 Chain breaking Antioxidants can be: Donor antioxidant, e.g. tocopherol, ascorbate, uric acid, … Sacrificial antioxidant, e.g. nitric oxide
Slide 26 - 26 Peroxyl Radicals as Targets RH + ROO  ROOH + R R + O2  ROO  The chain reaction can also be broken by intercepting R. In biology this is rare, but in the polymer industry it can be very important. Peroxyl radicals, ROO, are often the chain-carrying radical.
Slide 27 - 27 Terminating the Chain, Peroxyl Radicals as Targets Tocopherol, a donor antioxidant - LOO + TOH ¾¾® LOOH + TO Nitric oxide, a sacrificial antioxidant - LOO + NO ¾¾® LOONO
Slide 28 - 28 Characteristics of a Good Chain-breaking Antioxidant a. Both Antioxidant & Antiox should be relatively UN-reactive b. Antiox - decays to harmless products c. Does not add O2 to make a peroxyl radical Renewed (Recycled) – somehow If the chain-breaking antioxidant is a hydrogen atom donor, it should be in the middle of the pecking order.
Slide 29 - 29 The Pecking Order Buettner GR. (1993) Arch Biochem Biophy. 300:535-543. Antioxidants have reduction potentials that places them in the middle of the Pecking order. This location in the pecking order provides antioxidants with enough reducing power to react with reactive oxidizing species. At the same time they are too weak to initiate reductive reactions. LOO + TOH ¾¾¾® LOOH + TO Termination
Slide 30 - 30 The Pecking Order Buettner GR. (1993) Arch Biochem Biophy. 300:535-543. Depending on their reduction potential, antioxidants can recycle each other. For example, ascorbate with a reduction potential of +282 mV can recycle TO (+480 mV) and urate- (+590 mV).
Slide 31 - 31 Donor Antioxidant - Vitamin E Recycling reaction with ascorbate Reaction with lipid peroxides: LOO + TOH  LOOH + TO TO
Slide 32 - 32 Donor Antioxidant – Uric Acid Uric acid is produced by the oxidation of xanthine by xanthine oxidase. At physiological pH it is ionized to urate. Normal urate concentrations in human plasma range from 0.2 – 0.4 mM. Ames BN et al. (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer. A hypothesis. Proc. Natl Acad Sci. USA 78, 6858.
Slide 33 - 33 Uric Acid Reacts with Peroxyl Radicals k = 3 x 106 M-1 s-1 ROO + UH2-  ROOH + UH- Recycling by Ascorbate: k = 1 x 106 M-1 s-1 UH- + AscH-  UH2- + Asc -
Slide 34 - 34 Chain Breaking Antioxidant Sacrificial – Nitric Oxide
Slide 35 - 35 Nitric Oxide as Antioxidant Preventive: NO coordinates with heme-iron, Chain-breaking: NO can react with oxyradicals: NO upregulates systems that contribute to the antioxidant network: heme oxygenase, ferritin, hsp70, and -glutamylcysteine synthetase We have used this for centuries in food preservation, the "sausage" effect.
Slide 36 - 36 Nitric Oxide as Chain-Breaking Antioxidant in Lipid Peroxidation
Slide 37 - 37 Chain Breaking Antioxidant – Nitroxide Example nitroxide A possible antioxidant cycle for a nitroxide
Slide 38 - 38 Retarders vs Antioxidant Retarders suppress oxidations only slightly compared to a true antioxidant. A retarder is only able to make a significant change in the rate of oxidation of the bulk when present in relatively large amounts. Retarders are often confused with antioxidants.
Slide 39 - 39 Kinetic Comparison of Antioxidant and Retarder 1. The rate constants for nearly all reactions of HO in biology are 109 – 1010 M-1 s-1. Thus, everything reacts rapidly with it and it will take a lot of a “antioxidant” to inhibit oxidation of the bulk. 2. Comparing rates: Rate (HO + Bulk) = kb [Bulk] [HO] Rate (HO + Antiox) = ka [Antiox] [HO] Theorem: There are no true antioxidants for HO, only retarders. Proof:
Slide 40 - 40 Antioxidant vs Retarder 3. If we want 98% of the HO to react with an “antioxidant” AND have only a little bit of antioxidant (1% of bulk), then using RateBulk = kb [Bulk] [HO] RateAntiox = ka [Antiox] [HO] we have 2 = kb [99%] [HO] 98 = ka [1%] [HO] then, ka = 5 000 kb
Slide 41 - 41 Antioxidant vs Retarder 4. If ka = 5 000 kb and kb = 2 x 109 M-1 s-1, then ka must be 1 x 1013 M-1 s-1 5. No way, not in water. In H2O k must be < 1011 M-1 s-1 6. Because the a rate constant of 1013 M-1 s-1 in H2O is not possible and is 100x larger than the upper limit for a rate constant in water, there are no true antioxidants for HO, only retarders. 7. QED
Slide 42 - 42 Retarder Oxidation Time More retarder and lots of it. Oxidation products without retarder Oxidation with retarder [Retarder] Oxidation products with retarder
Slide 43 - 43 Antioxidant - no recycling Oxidation Time Lag time due to kinetic advantage Oxidation without antioxidant Oxidation with antioxidant [Antioxidant]
Slide 44 - 44 What is a practical kinetic advantage? Rate (LOO + Antiox) = ka [Antiox] [LOO] = ka’ [LOO] Rate (LOO + Bulk) = kb [Bulk] [LOO] = kb’ [LOO] where ka’ = ka [Antiox] and kb’ = kb [Bulk] If 1% “leakage” (damage) is acceptable, then ka’ = 100 kb’ If 0.01%, then ka’ = 10 000 kb’ Compare the pseudo first-order rate constants.
Slide 45 - 45 LDL and TOH Compare the pseudo first-order rate constants. Rate (LOO + PUFA ) = 40 M-1 s-1 [PUFA] [LOO] Rate (LOO + TOH ) = 105 M-1 s-1 [TOH] [LOO] If [PUFA] in LDL  1.5 M & [TOH] in LDL  0.02 M,* then k’TOH = 30 k’PUFA Leakage about 3% Estimated from: Bowery VW, Stocker R. (1993) J Am Chem Soc. 115: 6029-6043
Slide 46 - 46 Parting Thoughts 1 To test a compound for possible efficacy as a donor, chain-breaking antioxidant, studying its reactions with ROO would be much more appropriate than with HO.
Slide 47 - 47 Parting Thoughts 2 Keep in mind that besides possible antioxidant activity, the primary bio-activity of the “antioxidant” may be very different. [C. Rice-Evans - next] Antioxidants come in all colors and flavors. Picture stolen from C. Rice-Evans.