Vitamin E was described in 1922 and its basic mecha-nism of action was elucidated in 1931. However, some new compounds with vitamin E activity have beendiscovered, and some unknown mechanisms of action of this vitamin invivohave been described in a research con-ducted in the last 20 years. Therefore, the present review provides a comprehensive, current view of vitamin E.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• antioxidancia MeSH
• lidé MeSH
• tokoferoly farmakologie   metabolismus   MeSH
• tokotrienoly MeSH
• vitamin E * chemie   farmakologie   metabolismus   MeSH
• Check Tag
• lidé MeSH

We compared the effect of alpha-tocopheryl succinate (TOS) on succinate-dependent respiration in rat liver mitochondria, homogenate and permeabilized hepatocytes in both a coupled and uncoupled state. In isolated mitochondria, a significant inhibitory effect was observed at a concentration of 5 microM, in liver homogenate at 25 microM and in permeabilized hepatocytes at 50 microM. The inhibitory effect of TOS on succinate respiration in an uncoupled state was less pronounced than in a coupled state in all the experimental models tested. When the concentration dependence of the TOS inhibitory effect was tested, the most sensitive in both states were isolated mitochondria; the most resistant were permeabilized hepatocytes.

• MeSH
• alfa-tokoferol metabolismus   farmakologie   MeSH
• buněčná membrána metabolismus   MeSH
• buněčné dýchání účinky léků   MeSH
• časové faktory MeSH
• energetický metabolismus účinky léků   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• jaterní mitochondrie účinky léků   metabolismus   MeSH
• karbonylkyanid-p-trifluormethoxyfenylhydrazon farmakologie   MeSH
• oxidativní fosforylace účinky léků   MeSH
• permeabilita buněčné membrány MeSH
• potkani Wistar MeSH
• respirační komplex II metabolismus   MeSH
• rozpřahující látky farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

AIMS: To assess the effect of mitochondrially targeted vitamin E (VE) analogs on mitochondrial function and biogenesis. RESULTS: Mitochondrially targeted vitamin E succinate (MitoVES) is an efficient inducer of apoptosis in cancer cells. Here, we show that unlike its untargeted counterpart α-tocopheryl succinate, MitoVES suppresses proliferation of cancer cells at sub-apoptotic doses by way of affecting the mitochondrial DNA (mtDNA) transcripts. We found that MitoVES strongly suppresses the level of the displacement loop transcript followed by those of mtDNA genes coding for subunits of mitochondrial complexes. This process is coupled to the inhibition of mitochondrial respiration, dissipation of the mitochondrial membrane potential, and generation of reactive oxygen species. In addition, exposure of cancer cells to MitoVES led to decreased expression of TFAM and diminished mitochondrial biogenesis. The inhibition of mitochondrial transcription was replicated in vivo in a mouse model of HER2(high) breast cancer, where MitoVES lowered the level of mtDNA transcripts in cancer cells but not in normal tissue. INNOVATION: Our data show that mitochondrially targeted VE analogs represent a novel class of mitocans that not only induce apoptosis at higher concentrations but also block proliferation and suppress normal mitochondrial function and transcription at low, non-apoptogenic doses. CONCLUSIONS: Our data indicate a novel, selective anti-cancer activity of compounds that act by targeting mitochondria of cancer cells, inducing significant alterations in mitochondrial function associated with transcription of mtDNA-coded genes. These changes subsequently result in the arrest of cell proliferation.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buněčné dýchání účinky léků   MeSH
• lidé MeSH
• membránový potenciál mitochondrií účinky léků   MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondrie účinky léků   fyziologie   MeSH
• myši transgenní MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• receptor erbB-2 genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cytochrome c is a multifunctional hemoprotein in the mitochondrial intermembrane space whereby its participation in electron shuttling between respiratory complexes III and IV is alternative to its role in apoptosis as a peroxidase activated by interaction with cardiolipin (CL), and resulting in selective CL peroxidation. The switch from electron transfer to peroxidase function requires partial unfolding of the protein upon binding of CL, whose specific features combine negative charges of the two phosphate groups with four hydrophobic fatty acid residues. Assuming that other endogenous small molecule ligands with a hydrophobic chain and a negatively charged functionality may activate cytochrome c into a peroxidase, we investigated two hydrophobic anionic analogues of vitamin E, α-tocopherol succinate (α-TOS) and α-tocopherol phosphate (α-TOP), as potential inducers of peroxidase activity of cytochrome c. NMR studies and computational modeling indicate that they interact with cytochrome c at similar sites previously proposed for CL. Absorption spectroscopy showed that both analogues effectively disrupt the Fe-S(Met(80)) bond associated with unfolding of cytochrome c. We found that α-TOS and α-TOP stimulate peroxidase activity of cytochrome c. Enhanced peroxidase activity was also observed in isolated rat liver mitochondria incubated with α-TOS and tBOOH. A mitochondria-targeted derivative of TOS, triphenylphosphonium-TOS (mito-VES), was more efficient in inducing H2O2-dependent apoptosis in mouse embryonic cytochrome c(+/+) cells than in cytochrome c(-/-) cells. Essential for execution of the apoptotic program peroxidase activation of cytochrome c by α-TOS may contribute to its known anti-cancer pharmacological activity.

• MeSH
• aktivace enzymů účinky léků   MeSH
• alfa-tokoferol analogy a deriváty   chemie   farmakologie   MeSH
• apoptóza účinky léků   genetika   MeSH
• buněčné linie MeSH
• cytochromy c chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• koně MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši knockoutované MeSH
• peroxidasa chemie   metabolismus   MeSH
• spektrofotometrie MeSH
• terciární struktura proteinů MeSH
• vazba proteinů MeSH
• vazebná místa genetika   MeSH
• vitaminy chemie   metabolismus   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

Tumor-initiating cells (TICs) often survive therapy and give rise to second-line tumors. We tested the plausibility of sphere cultures as models of TICs. Microarray data and microRNA data analysis confirmed the validity of spheres as models of TICs for breast and prostate cancer as well as mesothelioma cell lines. Microarray data analysis revealed the Trp pathway as the only pathway upregulated significantly in all types of studied TICs, with increased levels of indoleamine-2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme of Trp metabolism along the kynurenine pathway. All types of TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. IDO1 expression was regulated via both transcriptional and posttranscriptional mechanisms, depending on the cancer type. Serial transplantation of TICs in mice resulted in gradually increased IDO1. Mitocans, represented by α-tocopheryl succinate and mitochondrially targeted vitamin E succinate (MitoVES), suppressed IDO1 in TICs. MitoVES suppressed IDO1 in TICs with functional mitochondrial complex II, involving transcriptional and posttranscriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work indicates that IDO1 is increased in TICs and that mitocans suppress the protein.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• antigeny CD98 genetika   metabolismus   MeSH
• antitumorózní látky fytogenní farmakologie   MeSH
• indolamin-2,3,-dioxygenasa genetika   metabolismus   MeSH
• kynurenin metabolismus   MeSH
• lidé MeSH
• metabolické sítě a dráhy účinky léků   genetika   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   patologie   MeSH
• přenašeč velkých neutrálních aminokyselin 1 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• respirační komplex II genetika   metabolismus   MeSH
• signální transdukce MeSH
• tryptofan metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

To investigate the role of mitochondrial antioxidant capacity during increased susceptibility to heat accompanied by the aging, young and aged Wistar rats were exposed on heat for 60 min. After heat exposure, hepatic and brain mitochondria were isolated. Our results revealed changes in antioxidant enzyme activities in liver and brain mitochondria from young and to a greater extent in aged rats. Our measurements of MnSOD, GPx and GR activity indicate greater reactive oxygen species production from the mitochondria of aged heat exposed in comparison to young heat exposed rats. Also in the aged rats, the effect of alpha-tocopherol treatment in the prevention of oxidative stress occurred as a result of heat exposure, is less pronounced. Taken together, our data suggest that mitochondria in aged rats are more vulnerable and less able to prevent oxidative changes that occur in response to acute heat exposure.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• časové faktory MeSH
• enzymy metabolismus   MeSH
• glutathionperoxidasa metabolismus   MeSH
• glutathionreduktasa metabolismus   MeSH
• jaterní mitochondrie účinky léků   enzymologie   MeSH
• krysa rodu rattus MeSH
• mitochondrie účinky léků   enzymologie   MeSH
• mozek účinky léků   enzymologie   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• reakce na tepelný šok účinky léků   MeSH
• stárnutí metabolismus   MeSH
• superoxiddismutasa metabolismus   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The present study determined markers of oxidative and antioxidative activity in dog females affected with mammary gland tumour compared to healthy ones. The effect of additional vitamin E supplementation on oxidative and antioxidative status was evaluated as well. The study included 29 female dogs divided into 4 groups (groups 1 and 2 included females with a mammary gland tumour; groups 3 and 4 included healthy female dogs). Additional vitamin supplement containing α-tocopherol was given to the females of groups 1 and 4. Dogs from groups 1 and 2 were anaesthetized before surgery (ovariohysterectomy and mastectomy); anaesthesia was used also in group 3, but without performeing surgery. The content of vitamin E (free α-tocopherol), marker of antioxidative status, was measured in blood serum by liquid chromatography. The concentration of thiobarbituric acid reactive substances, marker of oxidative status, in serum and concentrations of protein and non-protein thiol groups, markers of oxidative and antioxidative status, in blood serum and in red blood cells were measured colorimetrically. In females with a mammary gland tumour from group 2, concentration of thiobarbituric acid reactive substances was significantly higher than 14 days after surgery and compared to healthy ones as well. In females with a mammary gland tumour from group 2, concentration of protein thiol groups in serum was significantly lower and concentration of non-protein thiol groups in serum was significantly higher than in healthy controls. The values of protein thiols in erythrocytes in females with mammary gland tumour from group 1 were significantly higher before supplementation with vitamin E. The present study revealed that females with a mammary gland tumour were more burdened with oxidative stress compared to healthy dogs. The removal of the mammary gland tumour led to improvement of oxidative and antioxidative status. This is the first report focusing on the effect of additional α-tocopherol supplementation on reducing oxidative stress by increasing antioxidative activity in females affected with mammary gland tumour; however, we did not prove it.

• MeSH
• alfa-tokoferol * farmakologie   krev   terapeutické užití   MeSH
• antioxidancia MeSH
• biologické markery * krev   MeSH
• hysterektomie MeSH
• látky reagující s kyselinou thiobarbiturovou izolace a purifikace   MeSH
• mastektomie MeSH
• nádory mléčné žlázy u zvířat * farmakoterapie   chirurgie   MeSH
• ovarektomie MeSH
• oxidační stres účinky léků   MeSH
• psi MeSH
• sulfhydrylové sloučeniny klasifikace   krev   MeSH
• vitamin E MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

OBJECTIVES: The effects of ascorbic acid and α-tocopherol pre-treatment on hypoxia induced changes in brain cortex excitability were tested in immature rats exposed chronically to simulated altitude of 7 000 m. METHODS: Rat pups were kept together with their mothers for 8 hours a day in hypobaric chamber since the day of the birth till the postnatal day 11 or 17. Each day immediately before placing to hypobaric chamber pups were pretreated intraperitoneally either with ascorbic acid (100 mg/kg) or α-tocopherol (1 500 mg/kg). Cortical afterdischarges were elicited by repeated stimulation of the right sensorimotor cortex. The duration of evoked cortical afterdischarges was analyzed. RESULTS: Duration of cortical afterdischarges progressively declines with age. Hypoxia prolonged the duration of afterdischarges in 12-, 18- and 25-day-old animals. Pretratment with ascorbic acid or α-tocopherol shorted afterdischarges duration in youngest experimental group when compared with animals exposed to hypoxia only. CONCLUSION: Hypoxia significantly affects the brain cortex excitability by prolonging afterdischarges duration. This effect differs with age. Antioxidant pre-treatment brought about shorter duration of cortical afterdischarges only in the youngest experimental group. The antioxidant effect is therefore age dependent.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• epilepsie farmakoterapie   metabolismus   patofyziologie   MeSH
• evokované potenciály účinky léků   MeSH
• krysa rodu rattus MeSH
• kyselina askorbová farmakologie   MeSH
• mozková hypoxie farmakoterapie   metabolismus   patofyziologie   MeSH
• mozková kůra účinky léků   růst a vývoj   metabolismus   MeSH
• novorozená zvířata MeSH
• oxidační stres účinky léků   fyziologie   MeSH
• těhotenství MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of α-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. RESULTS: MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorter-chain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. INNOVATION AND CONCLUSION: We conclude that MitoVES, a mitochondrially targeted analog of α-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing.

• MeSH
• alfa-tokoferol analogy a deriváty   farmakologie   terapeutické užití   MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• endoteliální buňky účinky léků   MeSH
• hojení ran účinky léků   MeSH
• inhibitory angiogeneze chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• mitochondriální DNA metabolismus   MeSH
• mitochondrie účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• nádory krevní zásobení   farmakoterapie   MeSH
• patologická angiogeneze farmakoterapie   MeSH
• proliferace buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Tokoferol-alfa-acetát nachází uplatnění jako léčivá látka (vitamin E) v perorálních, parenterálních i topických přípravcích. Záměrem článku není dopodrobna rozvádět terapeutické využití tokoferolů, ale podat základní informace o vlastnostech a použití dané látky a především představit příklady vhodných receptur, neboť tokoferol se stále v některých předpisech na individuálně připravované léčivé přípravky objevuje. Příprava může být snazší, protože tokoferol-alfa-acetát je od října 2010 k dispozici lékárnám jako farmaceutická substance pro individuální přípravu léčivých přípravků.

Alpha-tocopherol acetate has been used as medicinal substance (vitamin E) for peroral, parenteral and topical preparationes. The aim of the article is not to present the sometimes questionable therapeutic use of tocopherols but to provide basic information on the properties and use of this substance and to present suitable examples of formulas because tocopherol is still used in some prescriptions of extemporaneous preparations. The formulation can be easier now because alpha-tocopherol acetate has been available as a substance for extemporaneous preparation in pharmacies since October 2010.

• Klíčová slova
• individuální příprava, dithranol, Nasopanthil.,
• MeSH
• alfa-tokoferol farmakologie   škodlivé účinky   terapeutické užití   MeSH
• fixní kombinace léků MeSH
• lékové formy MeSH
• lidé MeSH
• příprava léků metody   MeSH
• tokoferoly aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH