Tocotrienols as Anti-Chlamydials
A while back, Dr. Stratton had sent me a few articles about tocotreinols. Periodically I get a slew of articles from him frequently without explanation in the email. I kind of take it as a test; it brings me back to my grad school habits, that my job is to figure out the significance of them to this whole Cpn project. I don’t think that he is trying to test me, but rather the Cpn links are obvious to him as he is so expert in the biochemistry and microbiological details. It doesn’t always occur to him that others may lack the advanced degree to discern his train of thought! Red (Dan), who has had conversations with Dr. Stratton regarding Cpn and rosacea, has similarly reported having conversations with the good doctor where he has missed half the information just scrambling to take notes and keep up.
Usually I follow up sometime later in a phone call, confess my ignorance, and get explanation for the connections of the articles to Cpn if it’s not obvious. Well this time I clearly “failed the test” as I never really understood the importance of tocotrienols to our Cpn project, nor posted the references. In my defense, the particular articles were more general in nature and didn’t specifically refer to Cpn or infections at all, so I saw it more as an FYI (For Your Information). Worse though, in retrospect, I actually confused tocotrienols with tocopherols, the more common Vit E supplement. Tocotreinols are not; repeat not the same as tocopherols. In fact, for our particular anti-chlamydial purposes, the tocopherols (regular Vitamin E) can interfere with the positive actions of the tocotreinols and should be taken hours apart.
Recently, while researching another topic entirely, I happened on a patent[i], and study,[ii] which described the anti-chlamydial nature of tocotreinols, especially of delta and gamma tocotrienol (tocotrienols like Vit E come in alpha, delta and gamma forms). Subsequent review showed references on tocotrienols as anti-inflammatory, neuroprotective, lowering cholesterol, countering lipid oxidation, anti-tumor, as they are apoptotic for a number of bacteria and for cancer cells, and other useful processes.
I decided to post this first in the forums, as it’s not at this point an “official” part of the CAP protocols at this point. If I get a recommendation from one of the Cpn doc’s I’ll move it to the Handbook, but it seems useful to open it to community scrutiny and comment at this point. Cpnhelp readers can decide for themselves as to the potential usefulness of adding this supplement to their regime. PLEASE DON’T READ THIS AS A RECOMMENDED CURE ALL AND GET ALL ENTHUSIASTIC! Just check it out, and we’ll accumulate some forum responses to see how it affects the CAP as folks experiment.
Tocotrienol As Anti-Chlamydial Agent
The one that really got my attention is a patent, US 20060241174 titled “Vitamin E tocotrienols inhibition of intracellularly obligate pathogen Chlamydia and methods of use” by Mueller; Anne; (Sunderland, MA); Stuart; Elizabeth; (Amherst, MA); Tan; Barrie; (Amherst, MA).
Dr. Stuart is a leading Chlamydiologist doing stellar work in this area along with her grad students. She is the author of the study, which found a significant percentage of viable Cpn in healthy blood donors referred to elsewhere on this site.[iii] The research in the patent is impeccable science to my reading, and worth a read to the technically minded. It is much like the Vanderbilt patents by Mitchell and Stratton in the clarity of explanation and thoroughness of the research. I will try to give a brief summary and let readers look it up themselves for the full read.
Using (delta & gamma) tocotrienol:
· To inhibit, prevent, and disrupt the developmental cell cycle and infection of Chlamydia” [iv]
· Reduce the number of chlamydial inclusions into host cells (the means by which Cpn enters the host cell) by tocotrienol’s interference with the use of cell membrane cholesterol by Cpn.
· Impede and suppress the initial infection by EB’s (the infectious Chlamydial Elementary Bodies).
· To inhibit development and replication of Chlamydia within the host cell.
Their work is specifically directed:
· At Chlamydia in circulating WBCs, including neutrophils, monocytes, lymphocytes, eosinophils, and basophils.
· To reduce the cholesterol level and chlamydial infection in hyperlipidemic patients
· To restrict cholesterol/lipids to restrict Chlamydia infection and growth.
· Reduce Chlamydia infections in cancer patients.
· To ward off pathogenic infections including Chlamydia via activation of antigen-presenting dendritic cells and T-lymphocytes.
· To resist opportunistic chlamydial infection of hypertensive patients, and thereby reduce the patient's blood pressure.
· To reduce cardiovascular risk factors associated with metabolic syndrome, and thereby reduce the risk of diabetes and concomitant or subsequent infection by Chlamydia.
Basically their research suggests that the tocotrienols interference in both the process by which Chlamydia enters the cell via hypothesized “lipid rafts,” and in the process by which Chlamydia hijacks cholesterol from the cells lipid transport mechanisms. Like ATP, Chlamydia cannot manufacture cholesterol itself, and but requires it for it’s own survival and replication. Tocotrienols appear to inhibit the entry of EB’s into the host cell, inhibit the conversion of EB’s to RB’s as well as the replication process of RB’s to EB’s. It does not, to my understanding of their explanation, does not prevent or limit the formation of the aberrant cryptic forms, although it appears to induce apoptosis of infected host cells as well as of tumor cells—both types of cells are highly cholesterol dependant.
This appears to be a pretty multifaceted supplement in regards to Chlamydia. And that doesn’t even cover the neuroprotective and other useful effects.
One of things I found in researching further is that it is critical to have a high delta, high gamma form of tocotrienol, and also that it not have any tocopherols which would interfere with it’s effects. Annatto is one of the few origins of tocotreinols that fit this profile. Note that the authors also have patented a proprietary method of annatto extraction to produce this kind of tocotrienol.
An overview article[v] notes that tocotrienol overall:
· Most powerful antioxidant of the vitamin E family.
· The most potent tocotrienol to activate anticancer effects.
· More effective at accumulating in cells compared to other tocotrienols.
· Most effective member of the vitamin E for reducing endothelial expression of adhesion molecules, thereby preventing the accumulation of inflammatory cells within the arterial wall.
· Most potent tocotrienol in inducing apoptosis (cell deaths) of human breast cancer cells. Delta-tocotrienol was twice as potent as of gamma-tocotrienol.
· Inhibits the excessive aggregation of blood platelets much more effectively than vitamin E or other tocotrienols.
Tocotrienols appear to exert significant neuroprotective affects, by both anti-oxidant and non-anti-oxidant pathways.[vi] Dietary tocotrienols do reach the brain, and so would be expected to exert this effect in brain tissue.[vii] Tocotrienols protected the brain against stroke- and glutamate-induced degeneration in rats.
Immune Enhancing, Anti-viral and Anti-Cancer Effects-
Tocotrienols and alpha tocopherol have been shown to increase Ig production in the spleen and mesentery lymphatics, and to regulate immune function as well as to affect the proliferation and function of spleen and MLN lymphocyte. [viii] Tumor inhibiting effects[ix] [x] as well as tumor inhibition specific to prostate cancer cell lines (guys, pay attention!)[xi] have also been found. This same study hints at antiviral effects of tocotrienols as they inhibited by inhibiting EBV EA expression
It is in the area of cardiac disease that the interest in tocotreinols has perhaps been highest. This appears to be the result of tocotrienols effect on lipid profiles and on oxidation of lipids as well as on the association of Chlamydia pneumonia with artherosclerotic plaques[xii] and the tocotrienol’s effect on Cpn as demonstrated by Muller, et al. There are a number of useful reviews that detail this highly researched area.[xiii] [xiv] Additionally, they have impact on blood sugar and diabetes.[xv]
Safety & Interactions
Dosage and safety cautions are sparser to come by. Delta-tocotrienol - The 21st Century Vitamin E? (ibid) notes:
What are the dosage, drug interactions, and safety information for tocotrienols? The effectiveness of tocotrienols for some specific indications requires using tocopherol-free, high delta-tocotrienol products at a proper dosage. For example, for lowering cholesterol, utilize the 90% delta-tocotrienol preparation and begin with a dosage of 50 mg tocotrienols. Recheck cholesterol levels in four to six weeks and alter dosage accordingly. If cholesterol levels drop into the normal range, the dosage can be reduced. If cholesterol levels do not change enough, the dosage can be increased to 100 mg per day. For best results take the tocotrienols with food and at least one hour away from any vitamin E.
Tocotrienols are extremely safe and no side effects have been reported.13 Given the effects on platelet aggregation, you will need to inform your physician of their use if you are going in for surgery, or taking the blood thinning drug Coumadin® (warfarin) or anti-platelet drugs like Ticlid® (ticlopidine).
However, doses of the form mentioned in the anti-Chlamydial patent range from 10 mg and 1000 mg per day. They also note:
It is likely that control and eradication of Chlamydia in humans will require tocotrienol supplementation for an extended period. In light of this, tocotrienols and other agents (such as tangeretin, nobiletin, EGCG, and resveratol; more in Example 7) in monotherapies or in combination are superior because of their lack of toxicity. In contrast, other drugs (such as statins) have sustained toxicities with chronic usage. (ibid)
We also don’t know to what degree use of tocotrienols produces die-off reactions or secondary porphyria increases. Certainly, the inhibition of EB inclusions should not produce any die-off reactions unless it renders EB’s trying to enter the cell more vulnerable to the immune system. You’d expect not much more than the “NAC flu” type of reaction, if that. Inhibition of conversion of EB’s to RB’s as well as of RB replication processes should also not create much reaction, depending on how much LPS or HSP60 endotoxin is being generated by Cpn during these processes. However, the apoptotic inducing features of tocotrienol could potentially generate secondary porphyria reactions if the bursting of host cells releases intracellular stores of accumulated porphyrins. My suspicion is that the latter occurs at higher dosing, but of course we don’t really know what higher dosing means.
So, dear readers, if any of you experiment with this supplement we expect a detailed report of your findings. Remember, it is the high delta-tocotrienol form that you will need to look for, and make sure it is not mixed with tocopherols, which you should probably be taking too but at a widely separated time. And you thought your med schedule was complicated already!
[i] By the way, if you are a Macintosh user there is a wonderful little free program called PatentDownloader which not only can searh both US and World patents, but downloads them, along with associated pictures and charts! Plus it has the cutest kitty icon. Whimsy is very important when doing research! http://www.oneriver.jp/PD/
[ii] D-199. Impact of Hypocholesterolemic Delta-Tocotrienol on Chlamydial Development In Vitro
A. M. Mueller1, B. Tan2, E. S. Stuart1;
University of Massachusetts, Amherst, MA, 2American River Nutrition, Inc., Hadley, MA.
Chlamydiae, inclusion-forming obligate intracellular bacteria, are associated with common pathologies including Alzheimer’s disease, atherosclerosis, coronary heart disease, asthma, and respiratory tract infections. Entry by Chlamydiae, including C. pneumoniae and most C. trachomatis genital tract serovars, involves cholesterol-rich lipid raft domains. These can contain caveolae, a key element in cholesterol homeostasis with which Chlamydia may associate at cholesterol-enriched plaque regions. We hypothesized that the hypocholesterolemic activity of delta-tocotrienol, a vitamin E compound, might impact infection by Chlamydia. Human mammary tumor (MCF-7, TMX2-28), epithelial (HEp-2), B-lymphocyte (JY), and murine macrophage (J774A.1) cell lines were incubated with delta-tocotrienol concentrations of 10-30 μmol/L for 6 h prior to infection by serovar K, a C. trachomatis strain of the sexually transmitted disease biovar. At intervals between 24-72 h, cells were fixed, then samples were assessed, and infected cells identified by immunofluorescent staining followed by quantitative flow cytometry and confocal microscopy. Detected infection levels for cells pretreated with delta-tocotrienol were decreased by >50%. In addition, confocal immunofluorescent microscopy demonstrated the concomitant occurrence of aberrant pathogen inclusion development, including an apparent failure of fusion among the individually internalized elementary body clusters, and the formation of notably smaller inclusions. Microscopic counts of large and small inclusions in the delta-tocotrienol vs. control cells showed decreases of 3- and 2-fold, respectively. For JY cells, flow cytometry showed that a decrease of Chlamydia-infected cells was at least 2-fold during an infection period of 72 h, with a 2.6-fold maximum at 36 h. Since lipids and lipid levels may be critical to Chlamydia infections in vivo, hyperlipidemic patients were assessed for blood cell borne Chlamydiae. The in vivo impact of dietary delta-tocotrienol on Chlamydia carriage is under examination in a clinical study with cholesterol-suppressive delta-tocotrienol.
The pictures on her lab webpage of chlaydia inclusions stained with florescent dye are worth a look, as are those on http://www.bio.umass.edu/micro/faculty/webley.html the page of Dr. Webley.
[iv] From the patent abstract: “Chlamydial infection levels in mouse macrophages treated with tocotrienol were decreased >50%, with concomitant aberrant pathogen development. The number of large and small inclusions in tocotrienol-versus-control cells was decreased 3-fold and 2-fold, respectively. When treated with delta tocotrienol, Chlamydia in human lymphocytes was inhibited by at least 2.6-fold in 1.5 days. Dietary delta tocotrienol inhibited Chlamydia infection and persistence in hypercholesterolemic patients with a corresponding drop in LDL. These studies demonstrate that tocotrienol lowers cholesterol, thus preventing or diminishing the cholesterol hijacking by Chlamydia obligatory for its infectivity and replication. Therefore, hypolipidemic agents used to treat cardiovascular diseases, metabolic syndrome, and diabetes are used as monotherapies, or in combination with tocotrienol to treat Chlamydia.”
[v] Delta-tocotrienol - The 21st Century Vitamin E? http://www.doctormurray.com/newsletter/1-06-2003.htm
Tocotrienols Molecular Siblings of Tocopherols with Unique Vitamin E Properties
By Geoffrey C. Kwiat, Ph.D. http://www.vrp.com/articles.aspx?ProdID=art340&zTYPE=2
[vi] J Neurochem. 2006 September; 98(5): 1474–1486.
Characterization of the potent neuroprotective properties of the natural vitamin E α-tocotrienol
Savita Khanna, Sashwati Roy, Narasimham L. Parinandi, Mariah Maurer, and Chandan K. Sen
Savita Khanna, Laboratory of Molecular Medicine, Davis Heart & Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210.
All author affiliations.
Corresponding Author: Prof. Chandan K. Sen 512 Davis Heart & Lung Research Institute 473 West 12™ Avenue The Ohio State University Medical Center Columbus, Ohio 43210 Tel. 614 247 7658 Fax 614 247 7818 Email: firstname.lastname@example.org
The natural vitamin E tocotrienols possess properties not shared by tocopherols. Nanomolar alpha-tocotrienol, not alpha-tocopherol, is potently neuroprotective (JBC 275:13049; 278:43508; Stroke 36:2258). On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. We sought to dissect the antioxidant-independent and –dependent neuroprotective properties of alphatocotrienol by using two different triggers of neurotoxicity, homocysteic acid (HCA) and linoleic acid. Both HCA and linoleic acid caused neurotoxicity with comparable features such as increased GSSG/GSH, elevated [Ca2+]i and compromised mitochondrial [Delta]ψ . Mechanisms underlying HCA-induced neurodegeneration were comparable to the path implicated in glutamate-induced neurotoxicity. Inducible activation of c-Src and 12-lipoxygenase (12-Lox) represented early events in that pathway. Over-expression of active c-Src or 12-Lox sensitized cells to HCA-induced death. Nanomolar alpha-tocotrienol protected. Knock-down of c-Src or 12-Lox attenuated HCA-induced neurotoxicity. Oxidative stress represented a late event in HCA-induced death. The observation that micromolar, but not nanomolar, alpha-tocotrienol functions as an antioxidant was verified in the model involving linoleic acid induced oxidative stress and cell death. Oral supplementation of alpha-tocotrienol to humans results in a peak plasma concentration of 3 micromolar. Thus, oral alpha-tocotrienol may be neuroprotective by antioxidant-independent as well as antioxidant-dependent mechanisms.
[vii] Tocotrienol: the natural vitamin E to defend the nervous system?
Davis Heart & Lung Research Institute, 473 West 12th Avenue, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. email@example.com
Vitamin E is essential for normal neurological function. It is the major lipid-soluble, chain-breaking antioxidant in the body, protecting the integrity of membranes by inhibiting lipid peroxidation. Mostly on the basis of symptoms of primary vitamin E deficiency, it has been demonstrated that vitamin E has a central role in maintaining neurological structure and function. Orally supplemented vitamin E reaches the cerebrospinal fluid and brain. Vitamin E is a generic term for all tocopherols and their derivatives having the biological activity of RRR-alpha-tocopherol, the naturally occurring stereoisomer compounds with vitamin E activity. In nature, eight substances have been found to have vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Often, the term vitamin E is synonymously used with alpha-tocopherol. Tocotrienols, formerly known as zeta, , or eta-tocopherols, are similar to tocopherols except that they have an isoprenoid tail with three unsaturation points instead of a saturated phytyl tail. Although tocopherols are predominantly found in corn, soybean, and olive oils, tocotrienols are particularly rich in palm, rice bran, and barley oils. Tocotrienols possess powerful antioxidant, anticancer, and cholesterol-lowering properties. Recently, we have observed that alpha-tocotrienol is multi-fold more potent than alpha-tocopherol in protecting HT4 and primary neuronal cells against toxicity induced by glutamate as well as by a number of other toxins. At nanomolar concentration, tocotrienol, but not tocopherol, completely protected neurons by an antioxidant-independent mechanism. Our current work identifies two major targets of tocotrienol in the neuron: c-Src kinase and 12-lipoxygenase. Dietary supplementation studies have established that tocotrienol, fed orally, does reach the brain. The current findings point towards tocotrienol as a potent neuroprotective form of natural vitamin E.
[viii] Biosci Biotechnol Biochem (1999) 63: 1697-702.
Dietary effect of tocopherols and tocotrienols on the immune function of spleen and mesentery
JY Gu, Y Wakizono, Y Sunada, P Hung, M Nonaka, M Sugano, K Yamada
Department of Bioscience and Biotechnology, Kyushu University, Fukuoka, Jap
The immunoregulatory effects of dietary alpha-tocopherol (Toc) and tocotrienols (T-3) on humoral and cell-mediated immunity and cytokine productions were examined in Brown Norway rats. We found that the IgA and IgG productivity of spleen and mesenteric lymph node (MLN) lymphocytes was significantly enhanced in the rats fed on Toc or T-3, irrespective of concanavalin A (Con A) stimulation of the lymphocytes. On the contrary, the IgE productivity of lymphocytes from the rats fed on Toc or T-3 was less without Con A stimulation, but was greater in the presence of Con A, especially in the T-3 group. Toc or T-3 feeding significantly decreased the proportion of CD4+ T cells and the ratio of CD4+/CD8+ in both spleen and MLN lymphocytes of the rats fed on Toc or T-3. The interferon-gamma productivity of MLN lymphocytes was higher in the rats fed on Toc or T-3 than in those fed on a control diet in the presence of Con A, while that of spleen lymphocytes was lower in the rats fed on Toc or T-3. In addition, T-3 feeding decreased the productivity of tumor necrosis factor-alpha of spleen lymphocytes, while it enhanced the productivity of MLN lymphocytes. These results suggest that oral administration of Toc and T-3 affects the proliferation and function of spleen and MLN lymphocytes.
Title:Inhibition of tumour promotion by various palm-oil tocotrienols.
Author:Goh, S H : Hew, N F : Norhanom, A W : Yadav, M
Citation:Int-J-Cancer. 1994 May 15; 57(4): 529-31
Inhibition of tumour promotion by various vitamin E compounds (tocopherols and
tocotrienols) and some of their dimers was examined by an in vitro assay utilizing the
activation of Epstein-Barr virus (EBV) early antigen (EA) expression in
EBV-genome-carrying human lymphoblastoid cells. The results reveal that gamma- and
delta-tocotrienols derived from palm oil exhibit a strong activity against tumour
promotion by inhibiting EBV EA expression in Raji cells induced by
12-O-tetradecanoylphorbol-13-acetate (TPA). However, alpha- and gamma-tocopherols
and dimers of gamma-tocotrienol or gamma-tocopherol lack this activity.
[x] Cancer Lett. 2005 Nov 18;229(2):181-91. Epub 2005 Aug 10.Click here to read Links
Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, Nishino H.
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto 602-0841, Japan. firstname.lastname@example.org
Tocotrienols have been reported to have higher biological activities than tocopherols. We investigated the antitumor effect of tocotrienols both in vivo and in vitro. Oral administration of tocotrienols resulted in significant suppression of liver and lung carcinogenesis in mice. In human hepatocellular carcinoma HepG2 cells, delta-tocotrienol exerted more significant antiproliferative effect than alpha-, beta-, and gamma-tocotrienols. delta-Tocotrienol induced apoptosis, and also tended to induce S phase arrest. On the other hand, gene expression analysis showed that delta-tocotrienol increased CYP1A1 gene, a phase I enzyme. Although further study will be necessary to investigate possible adverse effect, the data obtained in present study suggest that tocotrienols could be promising agents for cancer prevention.
Authors: William L. Stone; K. Krishnan; Sharon Campbell; EAST TENNESSEE STATE UNIV JOHNSON CITY
Abstract: In this study we demonstrated that vitamin E isoforms, tocopherols and tocotrienols, have variable growth inhibitory effects on both types of prostate cancer cell line models. The gamma isoforms are more effective than the alpha isoforms and the tocotrienols are more effective than the tocopherols. This study further showed that the vitamin E-mediated inhibition of cell proliferation is preferential for cancer cells at concentrations of about 40 M or lower. Delta-tocotrienol (DT3), in particular, is infective against normal prostate epithelial cells but highly effective against LNCaP cancer cells. Collectively, our data supports the view that tocotrienols, particularly DT3 may prove very useful as chemotherapeutic or chemopreventive agents for treating prostate cancer. Our next will be to initiate experiments in animal models and then to initiate clinical studies.
Biochem Biophys Res Commun. 2006 Jul 28;346(2):447-53. Epub 2006 Jun 2. Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells.
Srivastava JK, Gupta S.
Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA.
One of the requisite of cancer chemopreventive agent is elimination of damaged or malignant cells through cell cycle inhibition or induction of apoptosis without affecting normal cells. In this study, employing normal human prostate epithelial cells (PrEC), virally transformed normal human prostate epithelial cells (PZ-HPV-7), and human prostate cancer cells (LNCaP, DU145, and PC-3), we evaluated the growth-inhibitory and apoptotic effects of tocotrienol-rich fraction (TRF) extracted from palm oil. TRF treatment to PrEC and PZ-HPV-7 resulted in almost identical growth-inhibitory responses of low magnitude. In sharp contrast, TRF treatment resulted in significant decreases in cell viability and colony formation in all three prostate cancer cell lines. The IC(50) values after 24h TRF treatment in LNCaP, PC-3, and DU145 cells were in the order 16.5, 17.5, and 22.0 microg/ml. TRF treatment resulted in significant apoptosis in all the cell lines as evident from (i) DNA fragmentation, (ii) fluorescence microscopy, and (iii) cell death detection ELISA, whereas the PrEC and PZ-HPV-7 cells did not undergo apoptosis, but showed modestly decreased cell viability only at a high dose of 80 microg/ml. In cell cycle analysis, TRF (10-40 microg/ml) resulted in a dose-dependent G0/G1 phase arrest and sub G1 accumulation in all three cancer cell lines but not in PZ-HPV-7 cells. These results suggest that the palm oil derivative TRF is capable of selectively inhibiting cellular proliferation and accelerating apoptotic events in prostate cancer cells. TRF offers significant promise as a chemopreventive and/or therapeutic agent against prostate cancer.
Synthesis and study of the cancer cell growth inhibitory properties of alpha-, gamma-tocopheryl and gamma-tocotrienyl 2-phenylselenyl succinates.
Vraka PS, Drouza C, Rikkou MP, Odysseos AD, Keramidas AD.
University of Cyprus, Department of Chemistry, 1678 Nicosia, Cyprus.
Vitamin E succinate selenium-conjugated molecules were synthesized and their apoptogenic properties were evaluated. 4-Methyl-2-phenylselenyl succinate (4) was prepared by the reaction of sodium benzeneselenolate with 2-bromosuccinic anhydrite in methanol solution. The methyl ester was converted to the acid (5) by hydrolysis with aqueous hydrochloric acid. Reaction of the 2-phenylselenyl succinic anhydrite (6) with alpha-tocopherol (1a), gamma-tocopherol (1c), and gamma-tocotrienol (2c) in acidic conditions gave the respective esters. The free radical scavenging properties of alpha-tocopheryl-2-phenylselenyl succinate (7), gamma-tocopheryl-2-phenylselenyl succinate (8), and gamma-tocotrienyl-2-phenylselenyl succinate (9) were evaluated in comparison with those of alpha-tocopheryl succinate (10), gamma-tocopheryl succinate (11), and gamma-tocotrienyl succinate (12), respectively, and the free tocopherols and gamma-tocotrienol. Compounds 7-9 induced a statistically significant decrease in prostate cancer cell viability compared to 10-12, respectively, or 5, exhibiting features of apoptotic cell death and associated with caspase-3 activation. These data show that structural modifications of vitamin E components by 5 enhance their apoptogenic properties in cancer cells.
Gamma-tocotrienol metabolism and antiproliferative effect in prostate cancer cells.
Conte C, Floridi A, Aisa C, Piroddi M, Floridi A, Galli F.
University of Perugia, Department of Internal Medicine, Section of Applied Biochemistry and Nutritional Sciences, Via del Giochetto, 06126 Perugia, Italy. email@example.com
In this study, we evaluated the antiproliferative effect of tocotrienols (T3) and the presence of a specific vitamin E metabolism in PC3 and LNCaP prostate cancer cells. These cell lines are able to transform tocopherols (T) and T3 in the corresponding carboxyethyl-hydroxychromans metabolites (CEHCs). The extent of this metabolism and the inhibitory effect on cell growth followed the order of magnitude alpha-T<alpha-T3<gamma-T<gamma-T3. The partial inhibition of gamma-T3 metabolism by ketoconazole did not influence cell proliferation. These early findings may suggest that the transformation of vitamin E to CEHC is mostly a detoxification mechanism useful to maintain the malignant properties of prostate cancer cells.
[xii] J Nutr. 2001 Oct;131(10):2606-18.Click here to read Links
Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 ApoE-deficient mice.
Qureshi AA, Salser WA, Parmar R, Emeson EE.
Advanced Medical Research, Madison, WI 53719, USA. firstname.lastname@example.org
We are studying novel tocotrienols, which have a number of activities that might interfere with the formation of atherosclerotic plaques, including hypocholesterolemic, antioxidant, anti-inflammatory and antiproliferation effects. This study compared the effects of alpha-tocopherol, the tocotrienol-rich fraction (TRF(25)) and didesmethyl tocotrienol (d-P(25)-T3) of rice bran on the pathogenesis of atherosclerotic lesions in C57BL/6 apolipoprotein (apo)E-deficient (-/-) mice. These mice are an excellent model because they become hyperlipidemic even when they consume a low fat diet and they develop complex atherosclerotic lesions similar to those of humans. These compounds were also tested in wild-type C57BL/6 apoE (+/+) and (+/-) mice fed low or high fat diets. When a high fat diet was supplemented with alpha-tocopherol, TRF(25) or d-P(25)-T3 and fed to mice (+/+) for 24 wk, atherosclerotic lesion size was reduced 23% (P = 0.33), 36% (P = 0.14) and 57% (P < 0.02), respectively, and in mice (+/-) fed for 18 wk, lesions were reduced by 19% (P = 0.15), 28% (P < 0.01) and 33% (P < 0.005), respectively, compared with mice fed a control diet. A low fat diet did not cause atherosclerotic lesions in these mice. The low fat diet supplemented with TRF(25) or d-P(25)-T3 fed to apoE-deficient (-/-) mice for 14 wk decreased atherosclerotic lesion size by 42% (P < 0.04) and 47% (P < 0.01), respectively, whereas alpha-tocopherol supplementation resulted in only an 11% (P = 0.62) reduction. These results demonstrate the superior efficacy of tocotrienols compared with alpha-tocopherol. Although tocotrienols decreased serum triglycerides, total and LDL cholesterol levels, the decreases in atherosclerotic lesions seem to be due to the other activities. Serum tocol concentrations in various groups are also described. This is the first report of a significant reduction in the atherosclerotic lesion size in all three genotypes of apoE mice fed a novel tocotrienol (d-P(25)-T3) of rice bran. Dietary tocotrienol supplements may provide a unique approach to promoting cardiovascular health.
Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature.
Patrick L, Uzick M.
The current understanding of the origin of atherosclerosis is that of an inflammatory process that involves the acute phase response -an innate biological response to a disturbance in homeostasis -infection, inflammation, tissue injury, neoplasm, or immune disturbance. The activation of the acute phase response, signaled by interleukin-6, produces proteins (fibrinogen, C-reactive protein (CRP), serum amyloid A) that lead to inflammatory reactions. The tissues themselves contain elevated levels of acute phase proteins and cytokines resulting in a localized inflammatory effect. Localized inflammatory responses in the intimal layer of the arterial wall have been shown to be responsible for many of the aspects of intimal thickening and plaque disruption, leading to acute cardiovascular events. The predictive value of plasma C-reactive protein as a risk factor for cardiovascular events has led some researchers to support the use of CRP as a main cardiovascular risk assessment tool, along with total cholesterol:HDL ratios and homocysteine levels. The ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has recently brought into question the mechanisms of action of the statin drugs. Because these medications lower incidences of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, questions have been asked about whether they may work independently of LDL-lowering mechanisms. Red yeast rice contains a naturally-occurring statin (lovastatin) as well as other cholesterol-lowering compounds, some with antioxidant effects. Alpha-tocopherol also significantly lowers CRP levels in diabetics and nondiabetics, and minimizes other aspects of the acute phase response and inflammatory damage involved in atherosclerosis. This may account for alpha-tocopherol's positive effect on cardiovascular morbidity and mortality. Finally, polyphenolic compounds present in virgin olive oil also have anti-inflammatory and antioxidative effects in cardiovascular disease. The phenolic compounds in virgin olive oil may explain some of the protective effects found in epidemiological studies.
[xiv]Annatto Tocotrienols:Vitamin E Component Dramatically More Effective at Supporting Heart Health
By Barrie Tan, PhD and Anne Mueller, MSc http://www.vrp.com/articles.aspx?ProdID=art2147&zTYPE=2
[xv] Annatto Tocotrienols: Their Significant Role in Blood Sugar Control
By John Raimo, MS, RD http://www.vrp.com/articles.aspx?ProdID=art2169&zTYPE=2