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Slide 1 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C.
Slide 2 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome”
Slide 3 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations
Slide 4 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics.
Slide 5 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature.
Slide 6 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters)
Slide 7 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2
Slide 8 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target?
Slide 9 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place?
Slide 10 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3)
Slide 11 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L
Slide 12 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants
Slide 13 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS
Slide 14 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4)
Slide 15 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases
Slide 16 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis
Slide 17 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow
Slide 18 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine
Slide 19 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants?
Slide 20 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ•
Slide 21 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators?
Slide 22 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators? curcumin resveratrol epigallocatechin gallate Do we get enough of these “antioxidants” into tissues to be effective as scavengers? Do they act as antioxidants or have affects on signaling? There can be up to 1 μM in plasma from diet (13) But, they can: - act as pro-oxidants for EpRE signaling or caspase activation (14) modulators of protein kinases (15) Indeed, LY294002, the most selective inhibitor of PI3 kinase, is an analog of quercetin (16) Polyphenols quercetin LY294002
Slide 23 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators? curcumin resveratrol epigallocatechin gallate Do we get enough of these “antioxidants” into tissues to be effective as scavengers? Do they act as antioxidants or have affects on signaling? There can be up to 1 μM in plasma from diet (13) But, they can: - act as pro-oxidants for EpRE signaling or caspase activation (14) modulators of protein kinases (15) Indeed, LY294002, the most selective inhibitor of PI3 kinase, is an analog of quercetin (16) Polyphenols quercetin LY294002 (−)-Epicatechin 4‘-O-Methyl-epicatechin Apocynin 3‘-O-Methyl-epicatechin O2 O2• – NADPH oxidase •NO ONOO – Nitrate COMT Oxidation, nitration Arginine Citrulline iNOS eNOS From (17)
Slide 24 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators? curcumin resveratrol epigallocatechin gallate Do we get enough of these “antioxidants” into tissues to be effective as scavengers? Do they act as antioxidants or have affects on signaling? There can be up to 1 μM in plasma from diet (13) But, they can: - act as pro-oxidants for EpRE signaling or caspase activation (14) modulators of protein kinases (15) Indeed, LY294002, the most selective inhibitor of PI3 kinase, is an analog of quercetin (16) Polyphenols quercetin LY294002 (−)-Epicatechin 4‘-O-Methyl-epicatechin Apocynin 3‘-O-Methyl-epicatechin O2 O2• – NADPH oxidase •NO ONOO – Nitrate COMT Oxidation, nitration Arginine Citrulline iNOS eNOS From (17) Increases in Antioxidant Enzymes by Oxidant Stress another non-antioxidant function of “antioxidants” MnSOD CuZnSOD catalase GPx 1 Prdx 6 γ-glutamyl transpeptidase Glutamate cysteine ligase NAD(P)H:quinone oxidoreductase 1 Heme oxygenase 1
Slide 25 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators? curcumin resveratrol epigallocatechin gallate Do we get enough of these “antioxidants” into tissues to be effective as scavengers? Do they act as antioxidants or have affects on signaling? There can be up to 1 μM in plasma from diet (13) But, they can: - act as pro-oxidants for EpRE signaling or caspase activation (14) modulators of protein kinases (15) Indeed, LY294002, the most selective inhibitor of PI3 kinase, is an analog of quercetin (16) Polyphenols quercetin LY294002 (−)-Epicatechin 4‘-O-Methyl-epicatechin Apocynin 3‘-O-Methyl-epicatechin O2 O2• – NADPH oxidase •NO ONOO – Nitrate COMT Oxidation, nitration Arginine Citrulline iNOS eNOS From (17) Increases in Antioxidant Enzymes by Oxidant Stress another non-antioxidant function of “antioxidants” MnSOD CuZnSOD catalase GPx 1 Prdx 6 γ-glutamyl transpeptidase Glutamate cysteine ligase NAD(P)H:quinone oxidoreductase 1 Heme oxygenase 1 The myth of the specific hydroxyl radical scavenger Almost all organic compounds react with •OH near diffusion limited rates. Thus, no compound has significantly more •OH scavenging activity than just about any other. So, you would have to drown it in!
Slide 26 - Antioxidants Henry Jay Forman, Ph.D. University of California at Merced Sunrise Free Radical School, 2007 Society for Free Radical Biology and Medicine 14th Annual Meeting Washington, D.C. Issues for consideration 1- Kinetics and concentrations - relation to bioavailability 2- Will the antioxidant get to the right place? 3- Specificity for scavenging target ROS/RNS 4- Potential interactions with co-antioxidants 5- Can antioxidants function as pro-oxidants? 6- Modes of action - scavengers or cell signaling regulators 7- The “specific hydroxyl radical scavenger syndrome” where [Antioxidant] is the instantaneous activity of the antioxidant 1- Kinetics and concentrations Thermodynamics tells you what could happen with or without the need to input energy. ΔGo must be negative for a reaction to occur spontaneously But, ΔGo (or standard reduction potentials) does not tell you how fast anything happens- that is the subject of kinetics. Which reaction will occur more rapidly? where A is the frequency factor for the reaction, R is the universal gas constant, and T is the temperature. Lucknow, India Elevation 128 meters Qinghai-Tibet Railway: The highest point of the railway is 5,072 meters above sea level ΔG is negative But the Himalayas are the barrier (Mt. Everest rises to 8,848 meters) Enzymes accelerate reactions by decreasing ΔG‡ ΔG‡ Non-enzymatic ΔG Progress of reaction ΔG ΔG‡ Enzymatic GSH + H2O2 GSSG + H2O An example is the reaction between glutathione (GSH) and H2O2 1- Kinetics and concentrations relation to bioavailability So, will the [Antioxidant] and k both be high enough to prevent the oxidant from reacting with a biological target? Factors influencing bioavailability Absorption through GI tract Metabolism in liver and other tissues Carrier molecules e.g., for α-tocopherol LDL Solubility/partitioning into membranes 2- Will the antioxidant get to the right place? Examples of bioavailabilty issues Dietary ascorbate (vitamin C) approaches upper limit in plasma (1) Some studies of a tea polyphenol suggest effectiveness at < 1 μM (the plasma peak) but most show need of > 10 μM (2) Olive oil polyphenols reach at most 60 nM but are effective as scavengers only at > 50 μM (3) Lipid peroxidation a major target for antioxidants H2O LH OH Initiation L Antioxidants in defense against lipid peroxidation 3- Potential interactions with co-antioxidants Superoxide Dismutases Metalloproteins with at least one transition metal (Cu, Mn, Fe) Rate constants in the range of 109 M-1 s-1 Found in cytosol, nucleus and extracellular compartments 4- Specificity for scavenging ROS/RNS The Radical Sink R· GS· GSSG·¯ GS¯ O2 O2 ·¯ GSH O2 + H2O2 O2 R SOD GSSG RH2 H2O2 GSH modified from (4) Glutathione as an enzyme substrate NADPH NADP + GSH GSSG Glutathione Peroxidases Peroxiredoxin 6 Glutathione Reductase LOOH LOH PSSG PSH H 2 O 2 H 2 O Protein disulfide isomerases GSH Glutathione synthesis Thioredoxin in elimination of H2O2 Non-enzymatic Trx oxidation is slow Peroxynitrite is a substrate for GPx Ebselen (5) or Trx reductase with Ebselen or selenocystine PDTC, Pyrrolidinedithiocarbamate PDTC inhibits NF-κB DNA binding (6) PDTC is a pro-oxidant copper chelator (7) NAC, N-acetylcysteine NF-κB activation by thiol oxidation (8) Thiols 5- Can antioxidants function as pro-oxidants? α-tocopherol, vitamin E In the absence of a co-antioxidant, α-tocopherol can be a pro-oxidant (9) Cu2+ Vit . E• Cu+ Vit . E PUFA PUFA• PUFA• Vit . E• PUFA Vit . E CoQ CoQ• The vitamin E debate (7/1/07 issue of Free Radic Biol Med) Azzi (10) stated, that α-tocopherol : has a natural function in cell signaling is the precursor of a more active form, α-tocopheryl phosphate does not prevent oxidative damage in vivo or oxidative diseases Traber (11) stated that α- tocopherol: participates only in signaling pathways involving oxidative stress protects PUFA and membrane changes affecting signaling has no direct signaling role Commentary by Brigelius-Flohe and Davies, “Is vitamin E an antioxidant, a regulator of signal transduction and gene expression, or a 'junk' food?” 6- Scavengers or cell signaling regulators? curcumin resveratrol epigallocatechin gallate Do we get enough of these “antioxidants” into tissues to be effective as scavengers? Do they act as antioxidants or have affects on signaling? There can be up to 1 μM in plasma from diet (13) But, they can: - act as pro-oxidants for EpRE signaling or caspase activation (14) modulators of protein kinases (15) Indeed, LY294002, the most selective inhibitor of PI3 kinase, is an analog of quercetin (16) Polyphenols quercetin LY294002 (−)-Epicatechin 4‘-O-Methyl-epicatechin Apocynin 3‘-O-Methyl-epicatechin O2 O2• – NADPH oxidase •NO ONOO – Nitrate COMT Oxidation, nitration Arginine Citrulline iNOS eNOS From (17) Increases in Antioxidant Enzymes by Oxidant Stress another non-antioxidant function of “antioxidants” MnSOD CuZnSOD catalase GPx 1 Prdx 6 γ-glutamyl transpeptidase Glutamate cysteine ligase NAD(P)H:quinone oxidoreductase 1 Heme oxygenase 1 The myth of the specific hydroxyl radical scavenger Almost all organic compounds react with •OH near diffusion limited rates. Thus, no compound has significantly more •OH scavenging activity than just about any other. So, you would have to drown it in! References Blanchard, Am J Clin Nutr 66:1165;1997 Lambert, J Nutr 133:32625;2003 Vissers, Eur J Clin Nutr 58:955;2004 Winterbourn, Free Radical Biol Med 14:85;1993 Sies, Free Radic Biol Med 28:1451;2000 Brennan, Biochem J 320:975;1996 Nobel, J Biol Chem 270:26202;1995 Das, Am J Physiol 269:L588;199 Thomas, Arterioscler Thromb Vasc Biol 16:687,199 Azzi, Free Radic Biol Med 43:16; 2007 Traber, Free Radic Biol Med 43:4; 2007 Brigelius-Flohe, Free Radic Biol Med 43:2; 2007 Scalbert, J Nutrition 130:2073S;2000 Owuor, Biochem Pharmacol 64:765;2002 Williams, Free Radic Biol Med 36:838;2004 Vlahos, J Biol Chem 269:5241;1994 Steffen Biochem Biophys Res Commun 359:828;2007