*free radicals with oxygen 

*non-radical reactive substances that harm us: ex. H2O2

*can damage cellular components

*endogenous and environmental

*imbalance btwn production of ROS and body's capability to detoxify or repair

*Mitochondria reduces the oxygen molecules we breathe (>97%)

*O2  +  4 e- + 4 H+ → 2 H2O

*small amount is reduced by accepting a single e-, which produces superoxide anion, a ROS: O2-

What causes free radicals to form?

*exercise, esp aerobic

*trans-fatty acids made with PUFAs

*smoking

*alcohol

*lack of sleep

*toxins from foods, pesticides, herbicides, chemicals and additives

*pollution

*electro-magnetic radiation

*stress- emotional/physical

*Superoxide Anion: O2- 

*Hydrogen Peroxide: H2O2 

*Hydroxyl Radical: •OH

*Reactive enough to attack some molecules

*Mobile enough to get to all parts of cells

*Superoxide Dismutase converts to H2O2 + O2 

*Extracellular and cytosolic SOD: Cu and Zn

*Mitochondrial SOD: Mn

*not very reactive by itself at low concentration, but can cause some damage (uncharged, freely permeable)

*Most dangerous when undergoes Fenton Rxn:

H2O2 + Fe2+ --> OH- + OH· + Fe3+

*functions as a iron-oxidizing agent

*Glutathione peroxidase (GPX) found in plasma, cytoplasm, mitochondria

*H2O2 + 2 GSH  -->  GSSG + 2 H2O

*H2O2 gets reduced

*GSH gets oxidized

*Catalase mainly in cytosol and peroxisomes

*higher concentration needed for catalase activity

*2 H2O2  ->  2 H2O  + O2

*most reactive species in living organisms

*can interact with almost any other chemical species

*lifetime is brief 

*not mobile

*H2O2  +  O2-  -->  O2  +  OH-  +  ·OH

*free metal ions promote this fenton rxn

*2 e- transfers

* 1st loss of e- = SDHA radical (ascorbate radical)

*loss of 2nd e- is quick = DHA

Interconversion of AA and DHA: 

Electrons are lost sequentially

Vitamin C:

Antioxidant

*e- donor 

*reducing agent

*most important antioxidant in plasma and cells

*protects against free radicals or recycles radicals of vit E and GSH

*SDHA is dangerous, but DHA radical is stable and far less damaging

AA + O2·  --> DHA + H2O2

AA + H2O2 --> DHA + 2H2O

AA + ·OH -->SDHA + H2O

*GSH uses DHA reductase

*2SDHA radicals + 2GSH -> 2AA + GSSG

*DHA + 2GSH -> AA + GSSG

*Thioredoxin provides H's to DHA

*DHA + Trx-[SH]2 -> AA + Trx-S2

*Dismutation regenerates AA and DHA from SDHA

*2 SDHA radicals --> AA + DHA

*Niacin regenerates AA by NADP-dep reductase

*2 SDHA radicals + NAD(P)H  + H+ --> AA +   NAD(P)+

*Dihydrolipoic acid provides 2 H to DHA

*DHA + dihydrolipoic acid --> AA + lipoic acid

*Vit E: critical fat-soluble antioxidant esp important in stabilizing membranes

*Vit E donates an E (its antioxidant role) becoming the vit E radical

*Vit E regenerated when Vit C donates an E

*Low vit C = high lipid peroxidation

*Significant antioxidant

*Protects LDL from oxidation

*Reduces plasma and GI tract oxidants

*Maintains function of WBCs and platelets

*Key role in iron absorption (non-heme) by maintaining iron in Fe²⁺ state

Free Radical Theory of Disease/Aging

*Free rads- major players in a nunmber of diseases and aging

*Mitochondrial production of O₂- is a major contributor to endogenous free rad formation

*O₂- formation is inversely related to lifespan

*Calorie restriction associated with decreased O₂- formation

*Decreased O₂- formation associated with decreased oxidative tissue damage

* Conflicting Data

*It may reduce incidence, severity, and duration of common cold

*No diff btwn .05g and 1g

*Long term supplementation does not appear to prevent colds

*Increase intake of fruits and veg - decrease risk of some cancers

*High Vit C intake may have protective effects against cancers: oral, pharynx, esophagus, stomach

*Recent study: Vit C doesn't help against breast cancer

*High fruits and vegs, vit C and high vit C plasma concentration = decrease risk of heart disease

*Low vit C = increased total plasma cholestrol 

*High plasma vit C = high HDL

*Mechanisms are not clear

*from oxidative damage to proteins in lens

*high vit C may reduce cataracts and age-related macular degeneration

*Low vit C associated with higher heart rates at lactate threshold

*Vit C supplementation reduced incidence of post-race URTI

*Effects on Delayed-Onset Muscle Soreness?

*Vit C enhances the absorption of non-heme iron by reducing Fe₃₊ to Fe₂₊

*Excess iron can destroy the vit C

*Vit C stabilizes ferritin (iron storage form)

*High vit C intake can reduce serum Cu and ceruloplasmin

*Vit C decreases intestinal absorption of Cu

*Possibly cause Cu dissociation from ceruloplasmin (transport form)

*Aka Prolixin

*the co-administration of vit C and this antipsychotic agent may result in decreased plasma fluphenazine

Interactions with Estrogen or

Estrogen-containing oral contraceptives

*Large dose of vit C may cause false-neg urine glucose determinations

*No vit C should be ingested for 48-72 hrs b4 fecal occult blood tests

*3g of vit C with tylenol was shown to prolong the amount of time Tylenol stays in body

*Possibly toxic

*RDA for Men: 90mg/d

*RDA for Women: 75mg/d

*Smokers: +35 mg/d

*Nonsmokers regularly exposed to tobacco smoke are encouraged to ensure that they meet the RDA

*Diarrhea: increase fecal loss of vit C

*Surgery, acute and chronic inflammatory diseases, and burns: increase body's requirement for vit C

*Scurvy: can be fatal

*Result from impaired hydroxyproline and hydroxylysine synthesis needed for collagen formation

*Bleeding gums, petechiae, sublingual hemorrhages, easy bruising, impaired wound and fracture healing

*First symptoms: fatigue, joint pain

*UL: men/women: 2,000 mg/d

*Toxic levels can be obtained only from supplements 

*Supplements often have 1,000mg

*Abdominal pain and osmotic diarrhea

*Osmotic diarrhea- when unabsorbed, water-soluble solutes remain in bowel

*Kidney stones: oxalate (vit C metabolite) is main part of stones

*Uric acid stones also risk with large doses

*Decreases copper absorption, iron metabolism in some ppl

*Blood or plasma levels of Vit C

*Plasma

*Deficiency: <0.2mg/dL

*Tissue Saturation: 1mg/dL

*Recommended: 0.6-0.8mg/dL

*WBC content of vitamin better reflects body stores, but it's difficult to perform

*Humans can't synthesize vit C

*Vit C's ability to interconvert btwn its reduced and oxidized forms is the basis for its function in the body:

*Cofactor (monoxygenase, dioxygenase rxns)

*Vit C is an antioxidant that scavenges ROS

*Scurvey- classic def syndrome

*Toxicity= diarrhea, kidney stones

*Vit C and disease:

*May reduce oxidation of LDL

*May improve immune function in endurance athletes