Funkce v těle

Antioxidant role in CNS

• Brain consumes 20% of the total body oxygen
• High metabolic rate
• Readily oxidizable tissue
• Antioxidants in the brain are needed to maintain the redox balance [11]

Neurons can reach intracellular

• SVCT2 is preferentially expressed in neurons
• ascorbate concentrations of 10 mM
• Glutathione concentration of 2.5 mM
• Increase in the expression of mRNA related to the translation of SVCT2 in both neurons and astrocytes
• Proven in rats with induced cerebral ischemia
• Cellular protective mechanism [11]

Glia

• Concentration of ascorbate is 2.5 mM
• Glutathione is 3.8 mM [11]

Astrocytes

• DHA which enters the cell via GLUT1
• ascorbate concentrates through the intracellular reduction of DHA [11]

Antioxidant

• Oxiduje se na dehydroaskorbát
• Vstupuje do buňky, kde je opět redukován na askorbát
• Redukční schopnosti askorbátu
• Důležitý ochrannzý prvek vodního prostředí
• Důležité pro oko
• Chrání proteiny, lipidy, sacharidy, NK proti ox. stresu
• Donating electrons and preventing oxidation to keep iron and copper atoms in their reduced states [12]

Prevent lipid peroxidation in plasma

• ascorbate is more effective than
• Thiols, alpha-tocopherol, and urate [11]
• Higher the concentration of ascorbate in blood is
• The greater the time it is required to initiate lipid peroxidation with no pro-oxidant effects
• Even in ascorbate serum concentrations of 5 mM achievable only parenterally [11]

Interakce vic. C

Vit. E

• Velký význam v oku
• Redukuje tokoferolové radikály
• Obnovuje vit. E vázaný v membráně

Glutathion

• Velký význam v oku
• Ve vodním prostředí chrání vit. C glutathion

Vychytává

• Může být oxidován mnoha oxidanty jako např.:
• Halogeny
• chinolony
• Fenolovými radikály aj.

ROS

• Superoxidový radikál
• Hyroxylové radikály
• Hydrogen peroxid
• Singletový kylsík

Limity

• Nemůže přímo vych. vol. radikály z lipofilního prostředí membrán

apoB products

• A significant relationship between plasma ASC level and the sum of apoB products
• Specifically determined ASC concentration sensitively reflects oxidative stress in tissues

Cholesterol

• Kofaktor syntázy žlučových kyselin
• Co-factor for the 7-hydroxylase
• Catalyzing the conversion of cholesterol to 7-hydroxycholesterol
• Vit C deficiency may increase circulating levels of cholesterol (CHOL)
• By reducing its excretion through the bile [3]

• VitC supplementation
• Can reduce the concentration of lipids in circulation (TG and LDL-C) [3]

• Vitamin C protects LDL ex vivo against oxidation
• May function similarly in the blood [4]

Enzymy

• Electron donor for 11 enzymes [4]
• 3 z nich jsou jen u živočichů a hub [4]

Hormony štítné žlázy

• Synthesis and catabolism of tyrosine [12]
• 4-hydroxyphenylpyruvate dioxygenase
• Modulates tyrosine metabolism [12]

Hormony peptidové

• Peptidylglycine alpha-amidating monooxygenase
• Amidates peptide hormones
• By removing the glyoxylate residue from their c-terminal glycine residues
• Increases peptide hormone stability and activity [12]

Imunita

• Stimuluje tvorbu bílých krvinek
• Vitamin C distributes readily in high concentrations into immune cells
• Has antimicrobial and natural killer cell activities
• Promotes lymphocyte proliferation
• Is consumed quickly during infections [12]

Játra

Kofaktor detoxikačních eliminačních reakcí v játrech

Snížení oxidačního stresu hepatocytu

• Decrease mitochondrial ROS formation in liver

Stimulate the activity of antioxidant enzymes

• In rat liver mitochondria
• Manganese superoxide dismutase (SOD)
• Glutathione peroxidase (GPx) [3]

Katecholamiy

• Biosynthesis and modulation of neurotransmission
• Dopamine beta hydroxylase [12]
• Role in the synthesis of
• Dopamine
• Norepinephrine

Modulatory effect of ascorbate in short term

• Co-substrate for
• Tyrosine hydroxylase
• Dopamine-beta-hydroxylase

Long term effect

• Increased gene expression of tyrosine hydroxylase
• V.s. via increase in intracellular cAMP - just a hypothesis [11]

Pokusy

Ascorbate-deficient guinea pigs

• Had high dopamine + low norepinephrine levels
• Alterations in the catalysis mediated by dopamine-beta-hydroxylase
• Levels were normalized even with low ascorbate concentration in the brain [11]

Kolagen

• Vývoj kostí, zubů a chrupavek, hojení...
• Podporuje růst
• Kofaktor 3 enzymes in collagen hydroxylation [3]
• Hydroxylace hydroxylysinu a hydroxyprolinu [3]
• Hydroxylation allows the collagen molecule to assume its triple helix structure
• vitamin C is essential to the development and maintenance of
• Scar tissue
• Blood vessels
• Cartilage,... [12]

Prolyl-3-hydroxylase

Prolyl-4-hydroxylase

Lysyl hydroxylase

Metabolism of microsome

Neuronální funkce

• Support and the structure of the neurons
• The processes of differentiation
• Maturation
• Neuronal survival [11]
• Modulation of neurotransmission [1]

Diferenciace

• Differentiation of embryonic stem cells into neurons in vitro
• Associated with an increase in the expression of genes involved in this process [11]
• Cells treated with ascorbate significantly increased the expression of genes associated with the differentiation of neuronal and astrocytic cells:
• NeuroD,
• Notch,
• BMP2,
• BMP7 [11]
• vitamin E and glutathione
• Do not have the same effect as ascorbate on neuronal cell differentiation [11]
• ascorbate promotes and maintains the differentiation of dopaminergic cells derived from midbrain neural precursors in vitro
• Involved up to 92 genes upregulated
• And downregulation of 118 genes
• Varying according to the stage of cell differentiation [11]

Neurite formation in neurons

• Potentiating effect of 2-glucoside-L-ascorbic acid (ascorbate analog) on the nerve growth factor (NGF) [11]
• + expression of brain-derived neurotrophic factor (BDNF)
• Associated to the presence of ascorbate in cell culture
• BDNF activates the Ras-MAP kinase pathway
• Contributes to cell survival
• By enhancing the expression of the enzymes of the endogenous antioxidant system
• Superoxide dismutase (SOD)
• Glutathione peroxidase
• Glutathione reductase [11]

Oxygenázy

• Interacts with enzymes having either monooxygenase or dioxygenase activity
• Monooxygenases
• Dopamine b-monooxygenase
• Peptidyl-glycine a-monooxygenase [4]
• Incorporate a single oxygen atom into a substrate
• Incorporate dopamine-terminating peptide
• Incorporate glycine-terminating peptide [4]
• Dioxygenases
• Incorporate two oxygen atoms in two different ways
• 4-hydroxyphenylpyruvate dioxygenase
• Incorporates two oxygen atoms into one product [4]
• Other dioxygenase
• Incorporates one oxygen atom into succinate
• And one into the enzyme-specific substrate [4]

Učení se a paměť

• Injected doses of 60 and 120 mg/kg of ascorbic acid intraperitoneally to mice
• With drug-induced amnesia by diazepam and scopolamine
• To mice that acquired amnesia naturally with age
• Elevated plus maze and the passive avoidance test
• ascorbic acid improved learning and memory in old mice
• Protected the mice in the group that received the drugs [11]

• Combination of vitamin C and vitamin E
• Can have beneficial effects preventing memory alterations
• Not possible to demonstrate the reproducibility of these results nor their efficacy in human studies in dementia and Alzheimer's disease [11]

• vitamin C effects on learning and memory
• Are dependent on the redox balance state
• Low dose of vitamin C (50 mg/kg) to healthy rats
• Retention latency in the passive avoidance test decreased [11]
• Exposed a group of rats to an acute dose of ozone (0.7 ppm) without vitamin C
• Retention latency in the passive avoidance test also decreased
• Same dose of vitamin C to rats exposed to ozone
• The retention latency was similar to that of the control
• Protective effect of the vitamin [11]

• Lipid peroxidation levels in the hippocampus
• Relationship between the oxidative damage and the deficit in the passive avoidance test
• Pro-oxidant effect of low dose vitamin C in a redox equilibrium
• Antioxidant effect at any doses in an oxidative stress state [11]

Prooxidační působení

• V případě některých nádorových buněk
• Tvorba peroxidu vodíku (H2O2) [1]
• Díky vysokému obsahu laktátu a feritinu [1]
• Proniká do maligních buněk, které mají porušený systém antioxidační obrany [1]
• Nedostatečnou aktivitu katalázy a superoxiddismutázy a nejsou schopny H2O2 redukovat [1]
• Poškození jejich DNA a apoptóza [1]
• Cílený cytotoxický účinek askorbátu u nádorových buněk [1]
• U zdravých buněk je deklarován a klinickou praxí potvrzen jeho antioxidativní účinek (Deubzer et al., 2010; Chen et al., 2011; Riordan et al., 2003) [1]

• In vitro při reakci s volnými ionty kovů katalyz. vznik vol. radikálů

• Vysoké koncentrace v séru
• Vytěsnění Fe, Cu a dalších kovů z bílkovin
• Katalyzují Fentonovou reakcí vznik volných radikálů
• Riziko časnější aterosklerozy

• Pro-oxidant effect of vitamin C associated with the presence of free dissolved metals
• Dependent on the time at which it was administered

Interaction of ascorbate with free metals caused the tissue damage

• After injecting paraquat-dichloride intraperitoneally
• Increase in ethane exhalation (oxidative stress marker)
• Lung tissue damage under the microscope [11]
• 10 mg/kg of ascorbate were administered intravenously prior to the injection of paraquat dichloride
• Protective effect was observed
• Administered 1 h after the paraquat dichloride injection
• Both ethane and tissue damage had increased [11]

30 healthy volunteers 500 mg/day of vitamin C for 6 weeks x placebo

• Increase in 8-oxoadenine levels (DNA oxidative damage marker)
• Decrease in 8-oxoguanosine levels [11]

6 healthy volunteers

• Intravenous administration of 750 or 7500 mg of vitamin C
• Did not increase the levels of lipid peroxides
• Nor 8-oxoguanosine [11]

Susceptibility effect of different types of cancer cells

• Pharmacological doses (0.3–20 mM) of vitamin C in vitro
• Ability of ascorbate to produce H2O2 in the extracellular space
• Only when the ascorbyl radical levels were >100 nM [11]
• Production of H2O2 depended on the presence of redox-active metal centers of proteins
• Demonstrated a significant decrease in tumor cell growth and tumor weight due to a pro-drug effect of vitamin C [11]

Ascorbate autoxidation

• Concentration of dianionic ascorbate increases by a factor of 10 for every pH unit increase
• Increased susceptibility to auto-oxidation of dianionic ascorbate
• Does not occur under physiological pH [11]

V případě, že chceme podpořit terapii nádorů a využít prooxidační efekt vit. C

• Glutathione and supplements that increase glutathione (eg, n-acetyl cysteine)
• Should not be given on the same day
• Oxidative capacity be lowered [13]
• Other antioxidants, such as
• Quercetin,
• Curcumin,
• melatonin
• May interfere with the oxidative capacity of vitamin C [13]

• Mice with pancreatic cancer xenografts
• Intraperitoneal ascorbic acid (AA) at 4g/kg daily
• Reduced tumor volume by 42% [13]
• Addition of intraperitoneal GSH
• Inhibited the AA-induced tumor volume reduction [13]

Psychika

• Kofaktor biosyntézy neurotransmiterů, neuroendokrinních peptidů
• Norepinefrinu (noradernalinu)
• Dopaminu aj.

Recyklační metabolické dráhy

• Pyrimidines
• Deoxyribose moiety of deoxynucleosides
• Má tedy vliv na hladinu kyseliny močové ?

Sekrece gonadotropinů

• ascorbate as an inductor of the liberation of gonadotropins
• Luteinizing hormone
• Follicle-stimulating hormone [11]
• ascorbate released by the vesicles of the gonadotrope cells
• Recaptured by SVCT2 via an unknown mechanism
• Facilitates the entry of Ca2+ into the cell
• Interacts with calmodulin
• Induces an increase in the activity of neuronal nitric oxide synthase (nNOS)
• Nitric oxide (NO) activates guanylate cyclase
• Increasing the amount of cGMP
• CGMP activates the protein kinase C (PKC)
• Leading to exocytosis of gonadotropine [11]

Spalování energie - syntéza karnitinu

• Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation [12]
• Důležitý pro tkáňové dýchání
• Kofaktor 2 enzymů při syntéze karnitinu [4]
• Etha - N-trimethyl-L-lysine hydroxylase [12]
• Gamma -butyrobetaine hydroxylase [12]

Stabilizace aterosklerotického plátu

• Vitmaín C a tvorba kolagenu
• Pláty myší s nedostatkem vitaminu C obsahovaly významně méně kolagenu a měly větší tendenci k ruptuře [7]
• Pokles exprese intercelulární adhezivní molekuly-1 (ICAM-1)
• Diapedeza monocytů

CNS struktura

• Important role in the synthesis of collagen and elastin
• Blood vessels that supply the neural tissue
• Basal lamina [11]
• Inductor of myelination
• Mediated by Schwann cells [11]
• Adding ascorbate to cultures of Schwann cells with ganglion neurons favored the production of the
• Basal lamina
• Essential for the induction of myelination [11]
• protein zero mRNA (PZM)
• Major component of myelin
• The mRNA expression of this protein was not exclusive of the ascorbate culture [11]
• Myelination occurs in the presence or absence of ascorbic acid
• Differences under these culture conditions were dependent on laminin
• P38
• Member of the family of MAP kinases
• Important role during the early stages of myelination
• Induced by both ascorbate and laminin [11]

• Main effect of ascorbate on myelination
• Probably due to the maintenance of the structural integrity of the basal lamina [11]

Žaludek

• The concentrations of vitamin C in gastric juice
• Several fold higher (median, 249 mmol/l; range, 43-909 mmol/l)
• In the plasma of the same normal subjects only 39 mmol/l, 14-101 mmol/l [4]

• May prevent the formation of N-nitroso compounds
• Potentially mutagenic [4]

• High intakes of vitamin C
• Correlate with reduced gastric cancer risk
• Cause-and-effect relationship has not been established

Metabolismus železa

• Zlepšuje resorpci železa z GIT