ascorbate
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Mitochondrial oxidative damage contributes to a wide range of pathologies. One therapeutic strategy to treat these disorders is targeting antioxidants to mitochondria by conjugation to the lipophilic triphenylphosphonium (TPP) cation. To date only hydrophobic antioxidants have been targeted to mitochondria; however, extending this approach to hydrophilic antioxidants offers new therapeutic and research opportunities. Here we report the development and characterization of MitoC, a mitochondria-targeted version of the hydrophilic antioxidant ascorbate. We show that MitoC can be taken up by mitochondria, despite the polarity and acidity of ascorbate, by using a sufficiently hydrophobic link to the TPP moiety. MitoC reacts with a range of reactive species, and within mitochondria is rapidly recycled back to the active ascorbate moiety by the glutathione and thioredoxin systems. Because of this accumulation and recycling MitoC is an effective antioxidant against mitochondrial lipid peroxidation and also decreases aconitase inactivation by superoxide. These findings show that the incorporation of TPP function can be used to target polar and acidic compounds to mitochondria, opening up the delivery of a wide range of bioactive compounds. Furthermore, MitoC has therapeutic potential as a new mitochondria-targeted antioxidant, and is a useful tool to explore the role(s) of ascorbate within mitochondria.
- MeSH
- antioxidancia chemie farmakologie MeSH
- jaterní mitochondrie účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina askorbová chemie farmakologie MeSH
- lékové transportní systémy metody MeSH
- oxidace-redukce MeSH
- oxidační stres účinky léků MeSH
- potkani Wistar MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- cholesterol metabolismus MeSH
- kyselina askorbová MeSH
- morčata MeSH
- organická chemie MeSH
- Check Tag
- morčata MeSH
Health status is determined by the balance of oxidants and antioxidants which protects healthy cells against the threat of internal and external risk factors. Antioxidants such as ascorbate (vitamin C, ascorbic acid) are of fundamental importance in this respect. Ascorbate neutralizes potential damage caused by cellular oxidative stress which may be the greatest risk of damage to healthy tissue. Cellular oxidative stress is mediated by external factors (e.g. psychological stress, physical exertion, drugs, various diseases, environmental pollution, preservatives, smoking, and alcohol) and internal factors (products of cellular metabolism including reactive oxygen species). When the products of oxidative stress are not sufficiently neutralized, healthy cells are at risk for both mitochondrial and DNA damage. In the short term, cell function may deteriorate, while an increased production of proinflammatory cytokines over time may lead to the development of chronic inflammatory changes and diseases, including cancer. Although pharmaceutical research continues to bring effective chemotherapeutic agents to the market, a limiting factor is often the normal tissue and organ toxicity of these substances, which leads to oxidative stress on healthy tissue. There is increasing interest and imperative to protect healthy tissues from the negative effects of radio-chemotherapeutic treatment. The action of ascorbate against the development of oxidative stress may justify its use not only in the prevention of carcinogenesis, but as a part of supportive or complementary therapy during treatment. Ascorbate (particularly when administered parentally at high doses) may have antioxidant effects that work to protect healthy cells and improve patient tolerability to some toxic radio-chemotherapy regimens. Additionally, ascorbate has demonstrated an immunomodulatory effect by supporting mechanisms essential to anti-tumor immunity. Intravenous administration of gram doses of vitamin C produce high plasma levels immediately, but the levels drop rapidly. Following oral vitamin C administration, plasma levels increase slowly to relatively low values, and then gradually decay. With an oral liposomal formulation, significantly higher levels are attainable than with standard oral formulations. Therefore, oral administration of liposomal vitamin C appears to be an optimal adjunct to intravenous administration. In this review, the basic mechanisms and clinical benefits of ascorbate as an antioxidant that may be useful as complementary therapy to chemotherapeutic regimens will be discussed.
- Klíčová slova
- podpůrná léčba,
- MeSH
- kvalita života MeSH
- kyselina askorbová * aplikace a dávkování farmakologie imunologie MeSH
- lidé MeSH
- nádory * farmakoterapie imunologie MeSH
- nežádoucí účinky léčiv farmakoterapie prevence a kontrola MeSH
- oxidační stres fyziologie MeSH
- protinádorové látky škodlivé účinky MeSH
- reaktivní formy kyslíku škodlivé účinky MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- izoenzymy chemie izolace a purifikace metabolismus MeSH
- kyselina askorbová farmakologie MeSH
- malátdehydrogenasa chemie izolace a purifikace metabolismus MeSH
- molekulární sekvence - údaje MeSH
- molekulová hmotnost MeSH
- organely enzymologie MeSH
- Trichomonas vaginalis enzymologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- elektronová paramagnetická rezonance metody využití MeSH
- financování organizované MeSH
- imunologické faktory terapeutické užití MeSH
- ionty metabolismus MeSH
- kyselina askorbová analogy a deriváty farmakologie MeSH
- kyselina hyaluronová farmakologie metabolismus MeSH
- lidé MeSH
- měď farmakologie metabolismus MeSH
- penicilamin farmakologie MeSH
- reaktivní formy kyslíku farmakologie metabolismus MeSH
- revmatoidní artritida farmakoterapie MeSH
- volné radikály izolace a purifikace MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- abstrakty MeSH
