TOCOTRIENOLS VITAMIN E BEYOND TOCOPHEROLS 80377.indb 1 7/2/08 8:36:27 AM 80377.indb 2 7/2/08 8:36:27 AM TOCOTRIENOLS VITAMIN E BEYOND TOCOPHEROLS EDITED BY Ronald Ross Watson Victor R. Preedy Boca Raton London New York CRC Press is an imprint of the Taylor & Francis Group, an informa business 80377.indb 3 7/2/08 8:36:28 AM CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487‑2742 © 2009 by The American Oil Chemist’s Society (AOCS) CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid‑free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number‑13: 978‑1‑4200‑8037‑7 (Hardcover) This book contains information obtained from authentic and highly regarded sources. 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QU 179 T631 2008] QP772.T6T63 2008 612.3’99‑‑dc22 2008018922 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com 80377.indb 4 7/2/08 8:36:28 AM Contents Foreword............................................................................................................................................ix Acknowledgment...............................................................................................................................xi Part a Introduction and Overview Chapter 1 Tocotrienols:.A.Review.................................................................................................3 Alexander G. Schauss Chapter 2 Tocotrienols.in.Vitamin.E:.Hype.or.Science?.............................................................13 Neil E. Levin and Dallas L. Clouatre Part B Sources Chapter 3 Tocotrienols:.Distribution.and.Sources.Cereals—Role.in.Human.Health.................23 Henryk Zielinski Chapter 4 Tocotrienols.in.Plants:.Sources.and.Importance.........................................................43 Liva Harinantenaina Chapter 5 Vitamin.E:.Natural.vs..Synthetic................................................................................61 Amy Kosowski and Dallas L. Clouatre Part C Chemistry of tocotrienols Chapter 6 Angiogenesis.Inhibition..............................................................................................79 Kiyotaka Nakagawa, Akira Shibata, Phumon Sookwong and Teruo Miyazawa Chapter 7 Chemistry.of.Tocotrienols...........................................................................................85 Sanchita P. Ghosh, Martin Hauer-Jensen and K. Sree Kumar Part D Mechanisms of action Chapter 8 Antioxidant.Activity.of.Tocotrienols.in.Cells.and.Serum..........................................99 Rossella Simone and Paola Palozza  80377.indb 5 7/2/08 8:36:29 AM i Tocotrienols: Vitamin E Beyond Tocopherols Chapter 9 Antioxidant.Action.of.Tocotrienols.and.Tocopherols.in.Solution.and. Membranes:.Chemical.and.Physical.Effects.............................................................109 Yasukazu Yoshida and Etsuo Niki Chapter 10 Antiproliferative.and.Apoptotic.Effects.of.Tocotrienols.on.Normal.and. Neoplastic.Mammary.Epithelial.Cells......................................................................119 Paul W. Sylvester Chapter 11 DNA.Polymerase.Inhibition......................................................................................141 Yoshiyuki Mizushina, Hiromi Yoshida and Teruo Miyazawa Chapter 12 Tocotrienols.in.Altering.the.Expression.of.Adhesion.Molecules.............................149 Yuji Naito and Toshikazu Yoshikawa Chapter 13 Uptake,.Distribution.and.Protective.Action.of.Tocotrienols.in.Cultured.Cells........159 Noriko Noguchi, Yoshiro Saito and Etsuo Niki Part E Cancer Prevention and treatment Chapter 14 Anticancer.Effects.of.Tocotrienols.and.Tocopherols.Irrespective.of. Anti-Oxidative.Properties.........................................................................................171 Tomohiro Yano and Nantiga Virgona Chapter 15 Role.of.the.MevalonatePathway.in.Tocotrienol-Mediated.Tumor.Suppression........185 Huanbiao Mo and Charles E. Elson Chapter 16 Telomerase.Inhibition................................................................................................209 Takahiro Eitsuka, Kiyotaka Nakagawa and Teruo Miyazawa Part F Heart Disease Chapter 17 Tocopherol.and.Tocotrienols:.Role.in.Heart.Disease.Care.and.Prevention..............219 Vijaya Juturu Chapter 18 Tocotrienols.and.the.Regulation.of.Cholesterol.Biosynthesis...................................237 Jiao Cao, Wei Qi and Bao-Liang Song Chapter 19 Tocotrienols.in.Cardiometabolic.Diseases................................................................257 Barrie Tan and Anne M. Mueller 80377.indb 6 7/2/08 8:36:29 AM Contents ii Chapter 20 Tocotrienols.in.Hyperlipidemic.Conditions..............................................................275 Jahangir Iqbal and Mohammad Minhajuddin Chapter 21 Vitamin.E.Isomers,.Tocotrienols,.in.Cardioprotection.............................................285 Samarjit Das, Manika Das and Dipak K. Das Part G Metabolism and absorption Chapter 22 Absorption.and.Disposition.of.Tocotrienols.............................................................297 Kah-Hay Yuen, Bee-Hong Ng and Jia-Woei Wong Chapter 23 Metabolism.of.Tocopherols.and.Tocotrienols.and.Novel.Functions.of.Their. Metabolites................................................................................................................309 Qing Jiang Chapter 24 Tocotrienols.Activate.the.Steroid.and.Xenobiotic.Receptor.SXR.to.Modulate. Small.Molecule.Metabolism.....................................................................................331 Kameran R. Johnson, Tiffany Hsu and Bruce Blumberg Part H Health Promotion Chapter 25 Tocotrienols.in.the.Potential.Treatment.of.Infectious.Disease.................................343 Anne M. Mueller, Barrie Tan and Elizabeth S. Stuart Chapter 26 Tocotrienols.as.Natural.Neuroprotective.Vitamins..................................................361 Chandan K. Sen, Savita Khanna and Sashwati Roy Chapter 27 Gamma-Tocotrienol:.Potential.as.a.Countermeasure.against.Radiological. Threat........................................................................................................................379 K. Sree Kumar, Sanchita P. Ghosh and Martin Hauer-Jensen Index...............................................................................................................................................399 80377.indb 7 7/2/08 8:36:29 AM 80377.indb 8 7/2/08 8:36:29 AM Foreword Fat-soluble.vitamins.have.their.root.in.the.1913.discovery.by.Elmer.V..McCollum,.Thomas.B.. Osborne.and.Lafayette.B..Mendel,.who.isolated.a.growth-producing.substance.from.egg.yolks..The. substance.appeared.quite.different.from.the.water-soluble.vitamins.already.discovered..In.1916,. McCollum.went.on.to.show.that.at.least.two.factors.were.responsible.for.the.normal.growth.of.rats,. factors.he.named.fat-soluble.A.and.water-soluble.B..McCollum.therefore.is.credited.with.initiating. the.custom.of.labeling.vitamins.by.letters..Vitamin.E.was.discovered.in.1922.in.green.leafy.veg- etables.by.University.of.California.researchers.Herbert.Evans.and.Katherine.Bishop..In.1924,.Sure. named.it.vitamin.E. In.1926,.the.February.15th.issue.of.TIME.magazine.reported.that: From.the.University.of.California,.Drs..Herbert.M..Evans.and.K..S..Bishop.last.week.announced. through.the.California.State.Board.of.Health.the.influence.of.the.mysterious.Vitamin.X.which.they. now.have.renamed.E..This.vitamin.stimulates.reproduction.in.animals,.prevents.sterility..It.is.a.complex. organic.compound,.like.the.four.other.known.vitamins,.and.occurs.in.lettuce,.wheat.germs,.alfalfa.and. egg.yolk..Because.humans.eat.largely.of.these.foods,.the.discovery.has.little.bearing.on.their.habits. Although.it.was.eight.decades.ago.that.we.thought.we.were.successful.in.demystifying.the. X-factor.in.vitamin.E,.it.is.my.observation.that.a.considerable.fraction.of.today’s.nutritional.com- munity.assume.that.vitamin.E.is.synonymous.with.tocopherol..In.fact,.natural.vitamin.E.includes. eight.chemically.distinct.molecules:.α-,.β-,.γ-.and.δ-tocopherol;.and.α-,.β-,.γ-.and.δ-tocotrienol.. However,.until.less.than.5.years.ago,.the.authoritative.Merck Manual.defined.vitamin.E.as.the.fol- lowing:.“Vitamin.E.(tocopherol).is.a.generic.term.for.compounds.that.have.a.6-chromanol.ring,.an. isoprenoid.sidechain,.and.the.biologic.activity.of.α-tocopherol..The.vitamin.E.group.contains.α-,. β-, γ-,.and.δ-tocopherols,.which.vary.in.extent.to.which.the.chromanol.ring.is.methylated.”.Note.the. omission.of.tocotrienols. In.the.current.literature,.more.than.95%.of.all.studies.on.vitamin.E.are.directed.toward.the. specific.study.of.α-tocopherol..The.other.forms.of.natural.vitamin.E.remain.poorly.understood.. The.abundance.of.α-tocopherol.in.the.human.body.and.the.comparable.efficiency.of.all.vitamin.E. molecules.as.antioxidants.led.biologists.to.neglect.the.non-tocopherol.vitamin.E.molecules.as.top- ics.for.basic.and.clinical.research..Recent.developments.warrant.a.serious.reconsideration.of.this. conventional.wisdom..The.tocotrienol.subfamily.of.natural.vitamin.E.possesses.powerful.neuropro- tective,.anti-cancer.and.cholesterol.lowering.properties.that.are.often.not.exhibited.by.tocopherols.. Current.developments.in.vitamin.E.research.clearly.indicate.that.members.of.the.vitamin.E.family. are.not.redundant.with.respect.to.their.biological.functions..α-Tocotrienol,.γ-tocopherol.and.δ-toco- trienol.have.emerged.as.vitamin.E.molecules.with.functions.in.health.and.disease.that.are.clearly. distinct.from.that.of.α-tocopherol..At.nanomolar.concentration,.α-tocotrienol,.not.α-tocopherol,. prevents.neurodegeneration..On.a.concentration.basis,.this.finding.represents.the.most.potent.of.all. biological.functions.exhibited.by.any.natural.vitamin.E.molecule..In.light.of.the.emergent.literature,. the.Merck Manual.seems.to.have.recognized.the.incompleteness.of.its.definition.cited.above.and. currently.has.included.tocotrienols.to.define.vitamin.E.as:.“Vitamin.E.is.a.group.of.compounds. (including.tocopherols.and.tocotrienols).that.have.similar.biologic.activities..The.most.biologically. active.is.α-tocopherol,.but.β-,.γ-,.and.δ-tocopherols,.four.tocotrienols.and.several.stereoisomers. may.also.have.important.biologic.activity.”.Here,.that.α-tocopherol.is.most.biologically.active.begs. further.consideration..For.example,.this.does.not.seem.to.be.true.for.the.neuroprotective.properties. of.vitamin.E. ix 80377.indb 9 7/2/08 8:36:30 AM