Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector

Ghosh, Sanchita; Kulkarni, S.; Hieber, Kevin; Toles, Raymond; Romanyukha, Lyudmila; Kao, Tzu Cheg; Hauer‐Jensen, Martin; Kumar, Krishna B.

doi:10.1080/09553000902985128

Cited by 144 publications

(198 citation statements)

References 36 publications

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“…Significant reduction in haematological indices following irradiation reported here is consistent with earlier reports on radiation-induced ablation of bone marrow [26,27]. Irradiation severely depleted reticulocytes, WBCs, neutrophils, lymphocytes, platelets and haematocrit counts, an effect that persisted 21-28 days after exposure.…”

Section: Discussionsupporting

confidence: 81%

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Satyamitra

Ney²,

Graves³

et al. 2012

The British Journal of Radiology

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Objective: The objective of this study was to investigate the correlation between in vivo d-tocotrienol (DT3) pharmacokinetics, pharmacodynamics and radiation protection, and to evaluate the effect of DT3 pre-treatment on radiation-induced alterations in apoptotic and autophagic pathways. Methods: We evaluated pharmacokinetics (plasma, 0.5 to 12 h) and pharmacodynamics (peripheral blood indices; day 3, 7, 10 and 14) after a single subcutaneous injection of 300 mg kg -1 DT3 in unirradiated CD2F1 mice. Next, we monitored 30-day post-irradiation survival (9.25 Gy) and haematopoietic recovery of DT3-treated mice (7 Gy) exposed to cobalt-60 c-irradiation. The effects of DT3 on irradiated bone marrow apoptosis and autophagy were determined by analyses of key caspases (3, 7, 9 and 8), beclin-1 and light chain 3 conversion. Results: Plasma concentration of DT3 reached ,195 mM (Cmax) 1 h after injection (Tmax), and DT3 was eliminated from plasma 12 h later. In unirradiated mice, DT3 significantly increased white blood cells (WBCs), neutrophils, lymphocytes (day 3 post DT3 injection) and platelets (day 7) by 1.5-to 2-fold, over vehicle-treated control. DT3 pre-treatment improved 30-day survival to 100% (,15% in control) and accelerated recovery of reticulocytes, platelets, WBCs, neutrophils, lymphocytes and monocytes in peripheral blood. DT3 reduced activation of caspase-8, caspase-3 and caspase-7, inherent to apoptosis, while increasing autophagy-related beclin-1 expression in irradiated bone marrow. Conclusion: These data indicate that DT3 stimulates multilineage haematopoiesis, protects against radiation-induced apoptosis downstream of the mitochondria and stimulates cytoprotective autophagy. Apart from a potent antioxidant activity, DT3 may elicit survival advantage following irradiation by enhancing haematopoiesis and modulating signalling pathways.

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Section: Discussionsupporting

confidence: 81%

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Satyamitra

Ney²,

Graves³

et al. 2012

The British Journal of Radiology

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“…GT3 ameliorates intestinal injury, enhances recovery of the intestine after irradiation, decreases vascular oxidative stress, and improves survival in animals subjected to total body irradiation (Felemovicius et al, 1995;Kulkarni et al, 2010;Berbée et al, 2011). GT3-conferred protection and reduction of mortality are associated with accelerated recovery of hematopoietic progenitor and white blood cells, neutrophils, monocytes, platelets, and reticulocytes after lethal radiation doses in mice (Ghosh et al, 2009;Kulkarni et al, 2010). It is noteworthy that the radioprotective action of GT3 against vascular injury is mediated through a HMG-CoA reductase-dependent mechanism (Berbée et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

γ-Tocotrienol Protects against Mitochondrial Dysfunction and Renal Cell Death

Nowak¹,

Bakajsova²,

Hayes³

et al. 2011

J Pharmacol Exp Ther

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Oxidative stress is a major mechanism of a variety of renal diseases. Tocopherols and tocotrienols are well known antioxidants. This study aimed to determine whether ␥-tocotrienol (GT3) protects against mitochondrial dysfunction and renal proximal tubular cell (RPTC) injury caused by oxidants. Primary cultures of RPTCs were injured by using tert-butyl hydroperoxide (TBHP) in the absence and presence of GT3 or ␣-tocopherol (AT). Reactive oxygen species (ROS) production increased 300% in TBHP-injured RPTCs. State 3 respiration, oligomycinsensitive respiration, and respiratory control ratio (RCR) decreased 50, 63, and 47%, respectively. The number of RPTCs with polarized mitochondria decreased 54%. F 0 F 1 -ATPase activity and ATP content decreased 31 and 65%, respectively. Cell lysis increased from 3% in controls to 26 and 52% at 4 and 24 h, respectively, after TBHP exposure. GT3 blocked ROS production, ameliorated decreases in state 3 and oligomycinsensitive respirations and F 0 F 1 -ATPase activity, and maintained RCR and mitochondrial membrane potential (⌬⌿ m ) in injured RPTCs. GT3 maintained ATP content, blocked RPTC lysis at 4 h, and reduced it to 13% at 24 h after injury. Treatment with equivalent concentrations of AT did not block ROS production and cell lysis and moderately improved mitochondrial respiration and coupling. This is the first report demonstrating the protective effects of GT3 against RPTC injury by: 1) decreasing production of ROS, 2) improving mitochondrial respiration, coupling, ⌬⌿ m , and F 0 F 1 -ATPase function, 3) maintaining ATP levels, and 4) preventing RPTC lysis. Our data suggest that GT3 is superior to AT in protecting RPTCs against oxidant injury and may prove therapeutically valuable for preventing renal injury associated with oxidative stress.

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“…Similar to tocopherols, tocotrienols have been distributed into α-, β-, γ-, and δ-forms (Falk and Munné-Bosch 2010;Mène-Saffrané and DellaPenna 2010). Tocotrienols have recently been attracting increasing of due to its superior biological properties over tocopherols, such as antioxidative, antihypercholesterolemic, anticancer, and neuroprotective activities (Ghosh et al 2009;Goh et al 1994;Khanna et al 2005;Qureshi et al 2002;Theriault et al 1999;Wada et al 2005). Tocopherols occur widely in plants and its α-form is especially abundant in the leaves of all plants (Szymanska and Kruk 2008).…”

mentioning

confidence: 99%

Generation of transgenic tobacco plants with enhanced tocotrienol levels through the ectopic expression of rice homogentisate geranylgeranyl transferase

Tanaka

Yabuta

Tamoi

et al. 2015

Plant Biotechnology

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Tocotrienols with three double bonds in the hydrocarbon tail are the major form of vitamin E in the seeds of most monocots and certain dicots. They have recently been attracting increasing attention for their various biological properties for human health. Homogentisate geranylgeranyl transferase (HGGT) catalyzes the committed step of tocotrienol biosynthesis. HGGT, except for enzyme from barley, has been not analyzed in detail, although cDNAs encoding HGGT have been isolated from barley, wheat, and rice. Since tocotrienol levels are higher in rice than in barley, rice HGGT (OsHGGT) may have superior enzymatic characteristics to those of barley HGGT. In the present study, we generated transgenic tobacco plants introducing OsHGGT cDNA into a nuclear genome and measured their tocopherol and tocotrienol levels. We demonstrated that the ectopic expression of OsHGGT enhanced tocotrienol levels without decreasing tocopherol levels in tobacco plants. The results of the present study may lead to a better understanding of the manipulation of vitamin E biosynthesis in leafy vegetables.

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Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector

Abstract: GT3 is a radioprotectant having a higher DRF than any other tocols. The protection it provides close to the gastro-intestinal range indicate that GT3 can be considered as an ideal radioprotectant meriting further drug development stages for the ultimate use in humans.

Cited by 144 publications

References 36 publications

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways

γ-Tocotrienol Protects against Mitochondrial Dysfunction and Renal Cell Death

Generation of transgenic tobacco plants with enhanced tocotrienol levels through the ectopic expression of rice homogentisate geranylgeranyl transferase

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