Inhibitors of Cholesterol Biosynthesis. 2. Hypocholesterolemic and Antioxidant Activities of Benzopyran and Tetrahydronaphthalene Analogs of the Tocotrienols

Pearce, Bradley C.; Parker, Rex A.; Deason, M. E.; Dischino, Douglas D.; Gillespie, Elizabeth; Qureshi, Asaf A.; Volk, K.; Wright, John J.

doi:10.1021/jm00030a012

Cited by 128 publications

(85 citation statements)

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“…At concentrations of 25-50 M, ␣-tocopherol is known to regulate signal transduction pathways by mechanisms that are independent of its antioxidant properties (8,9). Micromolar amounts of tocotrienol, but not tocopherol, have been shown to suppress the activity of hydroxy-3-methylglutaryl-coenzyme A reductase (10,11). The unsaturated side chain of tocotrienol allows for more efficient penetration into tissues that have saturated fatty layers such as the brain and liver (12).…”

mentioning

confidence: 99%

Molecular Basis of Vitamin E Action

Khanna

Roy

Ryu

et al. 2003

Journal of Biological Chemistry

261

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Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of ␣-tocotrienol, but not ␣-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049 -13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar ␣-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and L-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient ␣-tocotrienol. In silico docking studies indicated that ␣-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to ␣-tocotrienol as a potent neuroprotective form of vitamin E.

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confidence: 99%

Molecular Basis of Vitamin E Action

Khanna

Roy

Ryu

et al. 2003

Journal of Biological Chemistry

261

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“…The finding says that there are two antioxidative functional groups, the chromanol ring and the polyunsaturated phytol side chain in tocotrienols speaks for being a more potent antioxidant than tocopherols (Brigelius-Flohe and Traber 1999;Packer et al 2001;Wang and Quinn 1999). This structure-activity relationship indicated that in addition to the requirement of the prenyl side chain for HMG-CoA reductase (HMGR) suppression, changes in the methyl substitution on the chromanol ring may also lead to a divergent effect on HMGR activity (Pearce et al 1992a). In addition, the chirality at C-2 appears to play a minor role for sterolinhibitory activity.…”

Section: Structure-activity Relationship Of Tocotrienolsmentioning

confidence: 99%

“…In isolated human liver cells, a-tocotrienol (10 mM for 4 h) inhibited cholesterol synthesis by 32%. Interestingly, c-and d-tocotrienol, which lacked the 5-methyl substituents present in a-tocotrienol, were shown to possess significantly greater HMGR suppression (Pearce et al 1994). Tocotrienol not only of palm oil origin but also isolated from rice bran shows cholesterol-lowering properties (Chen and Cheng 2006;Pearce et al 1992b).…”

Section: Lipid-lowering Property Of Tocotrienols In Cardioprotectionmentioning

confidence: 99%

“…Tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMGCoA reductase and specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative nonsterol isoprenoid regulators derived from mevalonate. It is suggested that the farnesyl side chain and the methyl/ hydroxy substitution pattern of c-tocotrienol deliver a high level of HMG-CoA reductase suppression, unsurpassed by synthetic analogs studied (Pearce et al 1994) (Fig. 5).…”

Section: Lipid-lowering Property Of Tocotrienols In Cardioprotectionmentioning

confidence: 99%

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Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation

2011

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Tocotrienols are a class of vitamin E which modulates several mechanisms associated with cardioprotection, anti-cancer, anti-diabetic, and neuroprotection. Unlike other Vitamin E-like compounds, tocotrienols possess inimitable properties. Quite a lot of studies have determined the cardioprotective abilities of tocotrienols and have been shown to possess novel hypocholesterolemic effects together with an ability to reduce the atherogenic apolipoprotein and lipoprotein plasma levels. In addition, tocotrienol has been suggested to have an antioxidant, anti-thrombotic, and antitumor effect indicating that tocotrienol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer. The bioactivity exhibited is due to the structural characteristics of tocotrienols. Rich sources of tocotrienols which include rice bran, palm oil, and other edible oils exhibit protective effect against cardiovascular disorders. The conclusions drawn from the early literature that vitamin E group of compounds provides an inevitable role in cardioprotection is sustained in many more recent studies.

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“…[8][9][10] Micromolar amounts of tocotrienol suppress the activity of 3-hydroxy -3-methyl glutaryl coenzyme A (HMG-CoA) reductase, the hepatic enzyme responsible for cholesterol biosynthesis. 11,12 In animal cells also T3 inthibitc production of cholesterol by liver cells by suppressing 3-Hydroxy 3-Methyl Glutaryl coA Reductase enzyme (HMGR), a key enzyme in the stereogenic pathway. 13 Tocopherols do not share the cholesterol properties of Tocotrienol.…”

Section: Introductionmentioning

confidence: 99%