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Alpha Tocopherylquinone

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John P. Headrick – One of the best experts on this subject based on the ideXlab platform.

  • Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts.
    Antioxidants & redox signaling, 2009
    Co-Authors: Melissa E. Reichelt, Ana Shanu, Laura Willems, Paul K. Witting, Natasha A. Ellis, Michael R. Blackburn, John P. Headrick
    Abstract:

    We tested the impact of A1 adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia/45-min reperfusion (I/R). Wild-type hearts recovered approximately 50% of contractile function and released 8.2 +/- 0.7 IU/g of lactate dehydrogenase (LDH). A1AR deletion worsened dysfunction and LDH efflux (15.2 +/- 2.6 IU/g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and AlphaTocopherylquinone [Alpha-TQ; oxidation product of Alphatocopherol (Alpha-TOH)] increased sixfold. Elevations in Alpha-TQ were augmented by two- to threefold by A1AR deletion, whereas CE-O(O)H was unaltered. A(1)AR deletion also decreased glutathione redox status ([GSH]/[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I/R: fourfold elevations in HO-1 mRNA and activity were doubled by A1AR deletion. Broad-spectrum AR agonism (10 microM 2-chloroadenosine; 2-CAD) countered effects of A1AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A(2A), A(2B), and/or A3) can mediate similar actions. These data reveal that local adenosine engages A1ARs during I/R to limit oxidant damage and enhance outcome selectively. Control of Alpha-TOH/Alpha-TQ levels may contribute to A1AR-dependent cardioprotection.

  • Oxidant stress and damage in post-ischemic mouse hearts: effects of adenosine.
    Molecular and cellular biochemistry, 2006
    Co-Authors: Benjamin Hack, Paul K. Witting, Benjamin S Rayner, Roland Stocker, John P. Headrick
    Abstract:

    Despite the general understanding that ischemia-reperfusion (I/R) promotes oxidant stress, specific contributions of oxidant stress or damage to myocardial I/R injury remain poorly defined. Moreover, whether endogenous ‘cardioprotectants’ such as adenosine act via limiting this oxidant injury is unclear. Herein we characterized effects of 20 min ischemia and 45 min reperfusion on cardiovascular function, oxidative stress and damage in isolated perfused mouse hearts (with glucose or pyruvate as substrate), and examined whether 10 microM adenosine modified these processes. In glucose-perfused hearts post-ischemic contractile function was markedly impaired (< 50% of pre-ischemia), cell damage assessed by lactate dehydrogenase (LDH) release was increased (12 +/- 2 IU/g vs. 0.2 +/- 0.1 IU/g in normoxic hearts), endothelial-dependent dilation in response to ADP was impaired while endothelial-independent dilation in response to nitroprusside was unaltered. Myocardial oxidative stress increased significantly, based on decreased glutathione redox status ([GSSG]/[GSG + GSSH] = 7.8 +/- 0.3% vs. 1.3 +/- 0.1% in normoxic hearts). Tissue cholesterol, native cholesteryl esters (CE) and the lipid-soluble antioxidant Alphatocopherol (Alpha-TOH, the most biologically active form of vitamin E) were unaffected by I/R, whereas markers of primary lipid peroxidation (CE-derived lipid hydroperoxides and hydroxides; CE-O(O)H) increased significantly (14 +/- 2 vs. 2 +/- 1 pmol/mg in normoxic hearts). Myocardial AlphaTocopherylquinone (Alpha-TQ; an oxidation product of Alpha -TOH) also increased (10.3 +/- 1.0 vs. 1.7 +/- 0.2 pmol/mg in normoxic hearts). Adenosine treatment improved functional recovery and vascular function, and limited LDH efflux. These effects were associated with an anti-oxidant effect of adenosine, as judged by inhibition of I/R-mediated changes in glutathione redox status (by 60%), Alpha-TQ (80%) and CE-O(O)H (100%). Provision of 10 mM pyruvate as sole substrate (to by-pass glycolysis) modestly reduced I/R injury and changes in glutathione redox status and Alpha-TQ, but not CE-O(O)H. Adenosine exerted further protection and anti-oxidant actions in these hearts. Functional recoveries and LDH efflux correlated inversely with oxidative stress and Alpha -TQ (but not CE-O(O)H) levels. Collectively, our data reveal selective oxidative events in post-ischemic murine hearts, which are effectively limited by adenosine (independent of substrate). Correlation of post-ischemic cardiovascular outcomes with specific oxidative events (glutathione redox state, Alpha-TQ) supports an important anti-oxidant component to adenosinergic protection.

Todd A. Thompson – One of the best experts on this subject based on the ideXlab platform.

  • Antioxidants Abrogate AlphaTocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells
    PloS one, 2016
    Co-Authors: Alexandra M. Fajardo, Debra A. Mackenzie, Sarah L. Olguin, John K. Scariano, Ian Rabinowitz, Todd A. Thompson
    Abstract:

    Tocopherylquinone (TQ), the oxidation product of Alphatocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antiantigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen recereceptor protprotein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen recereceptor protprotein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

  • AlphaTocopherylquinone (TQ) is produced by the two-electron oxidation of the chromanol moiety of Alpha-tocopherol (AT).
    , 2016
    Co-Authors: Alexandra M. Fajardo, Debra A. Mackenzie, Sarah L. Olguin, John K. Scariano, Ian Rabinowitz, Todd A. Thompson
    Abstract:

    AlphaTocopherylquinone (TQ) is produced by the two-electron oxidation of the chromanol moiety of Alphatocopherol (AT).

  • AlphaTocopherylquinone, the major oxidation product of vitamin E, selectively decreases androgenic activity, growth, and viability of prostate cancer cells.
    Cancer Epidemiology and Prevention Biomarkers, 2006
    Co-Authors: Todd A. Thompson, Debra A. Mackenzie
    Abstract:

    A83 Results from epidemiological studies indicate that smoking and supplemental vitamin E (VE) may prevent prostate cancer. The mechanism for the combined action of smoking and supplemental VE on prostate cancer prevention is unknown. Chronic smoking produces a physiologic state of oxidative stress. The major oxidation product of VE is AlphaTocopherylquinone (ATQ), which is chemically distinct from VE. ATQ and VE were compared for their effects on prostate cancer cell growth, cell death, and on measures of androgenic activity in the LNCaP and PC3 human prostate carccarcinoma cell lines. ATQ produced a dose-dependent decrease in LNCaP growth, with a 26%, 36%, and 47% decrease in cell growth observed with physiologically relevant levels of 10, 20, and 30 μM, respectively, over 4 days. In contrast, treatment with VE up to 50 μM did not affect LNCaP growth over 4 days. Interestingly, neither ATQ nor VE significantly affected the growth of the androgen-independent PC3 cell line; whereas ATQ, but not VE, treatment resulted in 100% cell death in PC3 cells after reaching confluence for 48 hours. ATQ selectively inhibited androgen responsiveness in LNCaP cells compared to VE. For example, 25 μM ATQ inhibited androgen-induced expression from androgen-driven reporter vectors, whereas 25 μM VE had no effect. Similarly, ATQ significantly inhibited the androgen-induced expression of prostate specific antiantigen. In contrast, levels of VE up to 50 μM did not affect androgenic responses. LNCaP cells treated with 25 μM ATQ produced a 4-fold decrease in androgen recereceptor protprotein levels that was not observed following treatment with VE. A 2-fold decrease in androgen receptor mRNA was observed after ATQ treatment. In summary, ATQ, but not VE, was found to decrease growth, viability, and androgenic activity of human prostate cancer cells that may, in part, account for the prostate cancer preventive properties of concurrent smoking and supplemental VE. These observations will assist the development of effective VE-based strategies for prostate cancer prevention that do not necessitate smoking.

Achim Stocker – One of the best experts on this subject based on the ideXlab platform.

  • Molecular Mechanisms of Vitamin E Transport
    Annals of the New York Academy of Sciences, 2004
    Co-Authors: Achim Stocker
    Abstract:

    : Vitamin E is the most important lipid-soluble antioxidant in humans. Specific tocopherolbinding proteins favor the retention of the most potent vitamin E homologue, RRR-Alphatocopherol (RRR-Alpha-T) in man. The crystal structures of both the ligand-charged and the apo-forms of human Alphatocopherol transfer protein (Alpha-TTP) and of human supernatant protein factor (SPF) have been solved. The renewed interest in the biological function of tocopherol binders is based on the discovery of ataxia with vitamin E deficiency, a neurological disorder that is caused by genetic defects of the Alpha-TTP gene and/or vitamin E deficiency. The analysis of the crystal structure of Alpha-TTP provides the molecular basis of vitamin E retention in man. SPF has been reported to enhance cholesterol biosynthesis by facilitating the conversion of squalene to lanosterol. Nevertheless, the physiological role of SPF as well as its ligand specificity is not known. Investigations on the substrate specificity of SPF have uncovered binding of RRR-AlphaTocopherylquinone (RRR-Alpha-TQ). RRR-Alpha-TQ represents the major physiological oxidation product of RRR-Alpha-T. The three-dimensional overlay of the ligand-charged structures of SPF and Alpha-TTP indicates that ligand specificity in both proteins is mostly modulated by side-chain variations rather than by the backbone. Recent reports point towards the in vivo reduction of RRR-Alpha-TQ to RRR-Alpha-TQH(2) and its protective role in low-density lipoprotein oxidation. On the basis of these reports, it is proposed that SPF may enhance cholesterol biosynthesis indirectly by mediating the transfer of RRR-Alpha-TQ to low-density lipoprotein, thus reducing oxidation of low-density lipoprotein and its subsequent cellular uptake by scavenger receptors.

  • Supernatant protein factor in complex with RRR-AlphaTocopherylquinone: a link between oxidized Vitamin E and cholesterol biosynthesis.
    Journal of molecular biology, 2003
    Co-Authors: Achim Stocker, Ulrich Baumann
    Abstract:

    The vast majority of monomeric lipid transport in nature is performed by lipid-specific protein carriers. This class of proteins can enclose cognate lipid molecules in a hydrophobic cavity and transport them across the aqueous environment. Supernatant protein factor (SPF) is an enigmatic representative of monomeric lipid transporters belonging to the SEC14 family. SPF stimulates squalene epoxidation, a downstream step of the cholesterol biosynthetic pathway, by an unknown mechanism. Here, we present the three-dimensional crystal structure of human SPF in complex with RRR-AlphaTocopherylquinone, the major physiological oxidation product of RRR-Alphatocopherol, at a resolution of 1.95A. The structure of the complex reveals how SPF sequesters RRR-AlphaTocopherylquinone (RRR-Alpha-TQ) in its protein body and permits a comparison with the recently solved structure of human Alphatocopherol transfer protein (Alpha-TTP) in complex with RRR-Alphatocopherol. Recent findings have shown that RRR-Alpha-TQ is reduced in vivo to RRR-Alpha-TQH(2), the latter has been suggested to protect low-density lipoprotein (LDL) particles from oxidation. Hence, the antioxidant function of the redox couple RRR-Alpha-TQ/RRR-Alpha-TQH(2) in blocking LDL oxidation may reduce cellular cholesterol uptake and thus explain how SPF upregulates cholesterol synthesis.

Paul K. Witting – One of the best experts on this subject based on the ideXlab platform.

  • Endogenous adenosine selectively modulates oxidant stress via the A1 receptor in ischemic hearts.
    Antioxidants & redox signaling, 2009
    Co-Authors: Melissa E. Reichelt, Ana Shanu, Laura Willems, Paul K. Witting, Natasha A. Ellis, Michael R. Blackburn, John P. Headrick
    Abstract:

    We tested the impact of A1 adenosine receptor (AR) deletion on injury and oxidant damage in mouse hearts subjected to 25-min ischemia/45-min reperfusion (I/R). Wild-type hearts recovered approximately 50% of contractile function and released 8.2 +/- 0.7 IU/g of lactate dehydrogenase (LDH). A1AR deletion worsened dysfunction and LDH efflux (15.2 +/- 2.6 IU/g). Tissue cholesterol and native cholesteryl esters were unchanged, whereas cholesteryl ester-derived lipid hydroperoxides and hydroxides (CE-O(O)H; a marker of lipid oxidation) increased threefold, and AlphaTocopherylquinone [Alpha-TQ; oxidation product of Alpha-tocopherol (Alpha-TOH)] increased sixfold. Elevations in Alpha-TQ were augmented by two- to threefold by A1AR deletion, whereas CE-O(O)H was unaltered. A(1)AR deletion also decreased glutathione redox status ([GSH]/[GSSG + GSH]) and enhanced expression of the antioxidant response element heme oxygenase-1 (HO-1) during I/R: fourfold elevations in HO-1 mRNA and activity were doubled by A1AR deletion. Broad-spectrum AR agonism (10 microM 2-chloroadenosine; 2-CAD) countered effects of A1AR deletion on oxidant damage, HO-1, and tissue injury, indicating that additional ARs (A(2A), A(2B), and/or A3) can mediate similar actions. These data reveal that local adenosine engages A1ARs during I/R to limit oxidant damage and enhance outcome selectively. Control of Alpha-TOH/Alpha-TQ levels may contribute to A1AR-dependent cardioprotection.

  • Oxidant stress and damage in post-ischemic mouse hearts: effects of adenosine.
    Molecular and cellular biochemistry, 2006
    Co-Authors: Benjamin Hack, Paul K. Witting, Benjamin S Rayner, Roland Stocker, John P. Headrick
    Abstract:

    Despite the general understanding that ischemia-reperfusion (I/R) promotes oxidant stress, specific contributions of oxidant stress or damage to myocardial I/R injury remain poorly defined. Moreover, whether endogenous ‘cardioprotectants’ such as adenosine act via limiting this oxidant injury is unclear. Herein we characterized effects of 20 min ischemia and 45 min reperfusion on cardiovascular function, oxidative stress and damage in isolated perfused mouse hearts (with glucose or pyruvate as substrate), and examined whether 10 microM adenosine modified these processes. In glucose-perfused hearts post-ischemic contractile function was markedly impaired (< 50% of pre-ischemia), cell damage assessed by lactate dehydrogenase (LDH) release was increased (12 +/- 2 IU/g vs. 0.2 +/- 0.1 IU/g in normoxic hearts), endothelial-dependent dilation in response to ADP was impaired while endothelial-independent dilation in response to nitroprusside was unaltered. Myocardial oxidative stress increased significantly, based on decreased glutathione redox status ([GSSG]/[GSG + GSSH] = 7.8 +/- 0.3% vs. 1.3 +/- 0.1% in normoxic hearts). Tissue cholesterol, native cholesteryl esters (CE) and the lipid-soluble antioxidant Alpha-tocopherol (Alpha-TOH, the most biologically active form of vitamin E) were unaffected by I/R, whereas markers of primary lipid peroxidation (CE-derived lipid hydroperoxides and hydroxides; CE-O(O)H) increased significantly (14 +/- 2 vs. 2 +/- 1 pmol/mg in normoxic hearts). Myocardial AlphaTocopherylquinone (Alpha-TQ; an oxidation product of Alpha -TOH) also increased (10.3 +/- 1.0 vs. 1.7 +/- 0.2 pmol/mg in normoxic hearts). Adenosine treatment improved functional recovery and vascular function, and limited LDH efflux. These effects were associated with an anti-oxidant effect of adenosine, as judged by inhibition of I/R-mediated changes in glutathione redox status (by 60%), Alpha-TQ (80%) and CE-O(O)H (100%). Provision of 10 mM pyruvate as sole substrate (to by-pass glycolysis) modestly reduced I/R injury and changes in glutathione redox status and Alpha-TQ, but not CE-O(O)H. Adenosine exerted further protection and anti-oxidant actions in these hearts. Functional recoveries and LDH efflux correlated inversely with oxidative stress and Alpha -TQ (but not CE-O(O)H) levels. Collectively, our data reveal selective oxidative events in post-ischemic murine hearts, which are effectively limited by adenosine (independent of substrate). Correlation of post-ischemic cardiovascular outcomes with specific oxidative events (glutathione redox state, Alpha-TQ) supports an important anti-oxidant component to adenosinergic protection.

Debra A. Mackenzie – One of the best experts on this subject based on the ideXlab platform.

  • Antioxidants Abrogate AlphaTocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells
    PloS one, 2016
    Co-Authors: Alexandra M. Fajardo, Debra A. Mackenzie, Sarah L. Olguin, John K. Scariano, Ian Rabinowitz, Todd A. Thompson
    Abstract:

    Tocopherylquinone (TQ), the oxidation product of Alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

  • AlphaTocopherylquinone (TQ) is produced by the two-electron oxidation of the chromanol moiety of Alpha-tocopherol (AT).
    , 2016
    Co-Authors: Alexandra M. Fajardo, Debra A. Mackenzie, Sarah L. Olguin, John K. Scariano, Ian Rabinowitz, Todd A. Thompson
    Abstract:

    AlphaTocopherylquinone (TQ) is produced by the two-electron oxidation of the chromanol moiety of Alpha-tocopherol (AT).

  • AlphaTocopherylquinone, the major oxidation product of vitamin E, selectively decreases androgenic activity, growth, and viability of prostate cancer cells.
    Cancer Epidemiology and Prevention Biomarkers, 2006
    Co-Authors: Todd A. Thompson, Debra A. Mackenzie
    Abstract:

    A83 Results from epidemiological studies indicate that smoking and supplemental vitamin E (VE) may prevent prostate cancer. The mechanism for the combined action of smoking and supplemental VE on prostate cancer prevention is unknown. Chronic smoking produces a physiologic state of oxidative stress. The major oxidation product of VE is AlphaTocopherylquinone (ATQ), which is chemically distinct from VE. ATQ and VE were compared for their effects on prostate cancer cell growth, cell death, and on measures of androgenic activity in the LNCaP and PC3 human prostate carcinoma cell lines. ATQ produced a dose-dependent decrease in LNCaP growth, with a 26%, 36%, and 47% decrease in cell growth observed with physiologically relevant levels of 10, 20, and 30 μM, respectively, over 4 days. In contrast, treatment with VE up to 50 μM did not affect LNCaP growth over 4 days. Interestingly, neither ATQ nor VE significantly affected the growth of the androgen-independent PC3 cell line; whereas ATQ, but not VE, treatment resulted in 100% cell death in PC3 cells after reaching confluence for 48 hours. ATQ selectively inhibited androgen responsiveness in LNCaP cells compared to VE. For example, 25 μM ATQ inhibited androgen-induced expression from androgen-driven reporter vectors, whereas 25 μM VE had no effect. Similarly, ATQ significantly inhibited the androgen-induced expression of prostate specific antigen. In contrast, levels of VE up to 50 μM did not affect androgenic responses. LNCaP cells treated with 25 μM ATQ produced a 4-fold decrease in androgen receptor protein levels that was not observed following treatment with VE. A 2-fold decrease in androgen receptor mRNA was observed after ATQ treatment. In summary, ATQ, but not VE, was found to decrease growth, viability, and androgenic activity of human prostate cancer cells that may, in part, account for the prostate cancer preventive properties of concurrent smoking and supplemental VE. These observations will assist the development of effective VE-based strategies for prostate cancer prevention that do not necessitate smoking.