Oral toxicity of a tocotrienol preparation in rats

Nakamura, Hideaki; Furukawa, Fumio; Nishikawa, Akiyoshi; Miyauchi, Mutsumi; Son, Hwa–Young; Imazawa, Takayoshi; Hirose, Masao

doi:10.1016/s0278-6915(01)00025-4

Cited by 59 publications

(51 citation statements)

References 12 publications

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“…TRF was administered by gavage at dusk only during 1 wk before arginine administration and from day 5 after the last arginine injection. This dose stands below the level of toxicity (120 mg/kg) reported by Nakamura et al (26). Arginine pancreatitis was induced in the control group as above, but in place of TRF rats received coconut oil supplemented with 0.25 mg of ␣-tocopherol (both from Sigma-Aldrich, St. Louis, MO) to comply with the recommended vitamin E daily allowances issued by the National Research Council (18 mg/kg of rat diet) (45).…”

Section: Animalsmentioning

confidence: 52%

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

González

García

Samper

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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González AM, Garcia T, Samper E, Rickmann M, Vaquero EC, Molero X. Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis. Am J Physiol Gastrointest Liver Physiol 301: G846 -G855, 2011. First published August 18, 2011 doi:10.1152/ajpgi.00485.2010.-Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chroniclike pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, ␣-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-␤1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-␤1 (185 Ϯ 40 vs. 15 Ϯ 2 ng/ml; P Ͻ0.01) that was blunted by TRF (53 Ϯ 19; P Ͻ 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. ␣-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 Ϯ 0.3% vs. 0.2 Ϯ 0.2%), collagen network complexity (fractal dimension 1.52 Ϯ 0.03 vs. 1.42 Ϯ 0.01; P Ͻ 0.001), and inhomogeneity (lacunarity 0.63 Ϯ 0.03 vs. 0.40 Ϯ 0.02; P Ͻ 0.001), which were all reduced by TRF (1.3 Ϯ 0.4%, 1.43 Ϯ 0.02%, and 0.51 Ϯ 0.03%, respectively; P Ͻ 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r ϭ 0.88) and both parameters with pancreatic weight (r ϭ Ϫ0.91 and Ϫ0

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Section: Animalsmentioning

confidence: 52%

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis

González

García

Samper

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Not only being a more effective free radical scavenger, g-tocotrienol has also been shown to induce production of endogenous antioxidant enzymes such as SOD and GPx and to abate proinflammatory mediators, including TNF-a, IL-1b, IL-8, VCAM-1, and NF-kB (9-11) in vitro. Tocotrienols possess a favorable therapeutic index in rodents, with the no observed adverse effect level (NOAEL) reported up to a daily dose of 130 mg/kg in rats (equivalent to 260 mg/kg in mice) for 13 wk or up to 1 y (12)(13)(14). In the present study, we hypothesized that g-tocotrienol can protect against allergic airway inflammation via its antioxidative and anti-inflammatory properties.…”

mentioning

confidence: 90%

“…Because the NOAEL for tocotrienols was reported at 260 mg/kg daily in mice for 13 wk or up to 1 y (12)(13)(14), the highest oral dose of vitamin E isoforms in this study was capped at 250 mg/kg. a-Tocopherol (250 mg/kg), a-tocotrienol (250 mg/kg), d-tocotrienol (250 mg/kg), g-tocotrienol (30, 100, and 250 mg/kg), vehicle (oil emulsifier), or prednisolone (10 mg/kg) in 0.2 ml was given via oral gavage on days 7, 8, 9, 14, 15, and 16.…”

Section: Animalsmentioning

confidence: 99%

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

Peh

Chang

et al. 2015

The Journal of Immunology

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Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.

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“…An elevated platelet count is associated with an increased risk of thrombosis or inflammation whereas low platelet count prolongs bleeding (Fischbach and Duning III, 2009). In an earlier animal study, administration of 3% T3 in powdered diet preparation significantly reduced MCV, MCH and platelet count in animal (Nakamura et al, 2001). Later, Tasaki et al (2008) reported significant reduction of Hb level, haematocrit, MCV, and MCH in female rats after 2% T3 administration in diet.…”

Section: Ramdomised (N=32) (16 Males and 16 Females)mentioning

confidence: 93%