Antioxidants such as tocotrienols may protect against atherosclerosis since tissue injury from free radicals is a final common pathway of damage in arterial disease. In this study, the effects of tocotrienols on serum cholesterol, lipid peroxides, and aorta atheroma were assessed in rabbits fed an atherogenic diet for 12 weeks. Tocotrienols were more effective than tocopherols in preventing increases in serum LDL (p = 0.03) and total cholesterol (p = 0.008) levels in the cholesterol-fed rabbits. Elevation of serum lipid peroxides was effectively suppressed by tocotrienols (p = 0.01). Both tocopherols and tocotrienols offered significant protection against atheroma in the rabbit aorta, but tocotrienols had a stronger hypolipidaemic effect.

Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

Abstract

Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of [14C]acetate but not [3H] mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by [35S]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.

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Barley oil was extracted with hexane from the grain of a high oil waxy hull-less barley. Twelve male broiler chicks were fed corn-based diets with either 10% barley oil, 10% corn oil or 10% margarine ad libitum for ten days. Total plasma cholesterol concentration of the chicks fed barley oil was 34% lower (p < 0.05) than that of the chicks fed margarine. Plasma low density lipoprotein cholesterol concentration of chicks fed barley oil was 53% and 59% lower (p < 0.05) than those of chicks fed corn oil and margarine, respectively. Plasma high density lipoprotein cholesterol and triglyceride concentration of the barley oil group were similar to those of the margarine but higher (p < 0.05) than those of the corn oil group. Chicks fed the barley oil gained more (p < 0.05) body weight than those fed the corn oil and margarine. Barley oil had an effect in suppression of TC and LDLC in chicks compared to margarine. Barley oil suppressed LDLC but not HDLC in chicks compared to corn oil. A greater weight gain of the chicks fed barley oil suggested that these chicks had normally functioning digestion and absorption. alpha-Tocotrienol and gamma-tocotrienol content of the barley oil were 24 and 17 times greater, respectively, than those observed in the corn oil, while the same fractions were not detectable in the margarine. Polyunsaturated fatty acid content of the barley oil was more than threefold that of margarine. These data suggest that alpha-tocotrienol and polyunsaturated fatty acids are hypocholesterolemic components in barley oil.

Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

Oxidative modification of low density lipoproteins (LDL) and their unrestricted scavenger receptor-dependent uptake is believed to account for cholesterol deposition in macrophage-derived foam cells. It has been suggested that vitamin E that is transported by LDL plays a critical role in protecting against LDL oxidation. We hypothesize that the maintenance of sufficiently high vitamin E concentrations in LDL can be achieved by reducing its chromanoxyl radicals, i.e., by vitamin E recycling. In this study we demonstrate that: i) chromanoxyl radicals of endogenous vitamin E and of exogenously added alpha-tocotrienol, alpha-tocopherol or its synthetic homologue with a 6-carbon side-chain, chromanol-alpha-C6, can be directly generated in human LDL by ultraviolet (UV) light, or by interaction with peroxyl radicals produced either by an enzymic oxidation system (lipoxygenase + linolenic acid) or by an azo-initiator, 2,2′-azo-bis(2,4-dimethylvaleronitrile) (AMVN; ii) ascorbate can recycle endogenous vitamin E and exogenously added chromanols by direct reduction of chromanoxyl radicals in LDL; iii) dihydrolipoic acid is not efficient in direct reduction of chromanoxyl radicals but recycles vitamin E by synergistically interacting with ascorbate (reduces dehydroascorbate thus maintaining the steady-state concentration of ascorbate); and iv) beta-carotene is not active in vitamin E recycling but may itself be protected against oxidative destruction by the reductants of chromanoxyl radicals. We suggest that the recycling of vitamin E and other phenolic antioxidants by plasma reductants may be an important mechanism for the enhanced antioxidant protection of LDL.

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In this paper, we review the effects of rice bran oil (RBO), an unconventional oil recently introduced onto the Indian market for human use. RBO contains oleic acid (38.4%), linoleic acid (34.4%), and linolenic acid (2.2%) as unsaturated fatty acids, and palmitic (21.5%) and stearic (2.9%) acids as saturated fatty acids. The unsaponifiable fraction (4.2%) has total tocopherols (81.3 mg%), gamma-oryzanol (1.6%), and squalene (320 mg%). Oryzanol is a mixture of ferulic acid esters of triterpene alcohols such as cycloartenol (CA) (106 mg%) and 24-methylene cycloartanol (494 mg%). Studies on experimental rats demonstrated a hypolipidemic effect of RBO. The unsaponifiable fraction of RBO lowers cholesterol levels. Feeding phytosterols, CA, and 24-methylene cycloartanol in amounts present in RBO to hypercholesterolemic rats for 8 weeks indicates that CA alone reduces cholesterol and triglyceride levels significantly. Endogenous sterol excretion increases in animals given CA. The accumulation of CA in the liver inhibits cholesterol esterase activity, which in turn leads to reduction in circulating cholesterol levels. CA is structurally similar to cholesterol and may compete with the binding sites of cholesterol and sequestrate cholesterol, which is metabolized to its derivatives. RBO, which is rich in tocopherols and tocotrienols, may improve oxidative stability. Tocotrienols inhibit HMG CoA reductase, resulting in hypocholesterolemia. The hypolipidemic effect of RBO has also been established in human subjects. Thus, RBO could be a suitable edible oil for patients with hyperlipidemia.