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JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 The Bioinorganic Chemistry of Chromium i JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 The Bioinorganic Chemistry of Chromium John B. Vincent Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama, USA A John Wiley and Sons, Ltd., Publication iii JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 Thiseditionfirstpublished2013 (cid:2)C 2013JohnWiley&Sons,Ltd Registeredoffice JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester,WestSussex,PO198SQ,United Kingdom Fordetailsofourglobaleditorialoffices,forcustomerservicesandforinformationabouthowto applyforpermissiontoreusethecopyrightmaterialinthisbookpleaseseeourwebsiteat www.wiley.com. Therightoftheauthortobeidentifiedastheauthorofthisworkhasbeenassertedinaccordance withtheCopyright,DesignsandPatentsAct1988. 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Neitherthepublishernortheauthorshallbeliableforanydamagesarisingherefrom. LibraryofCongressCataloging-in-PublicationData Vincent,JohnB.(JohnBertram) Thebioinorganicchemistryofchromium/JohnB.Vincent. p.;cm. Includesbibliographicalreferencesandindex. ISBN978-0-470-66482-7(cloth) I.Title. [DNLM:1. Chromium–chemistry. 2. Chromium–therapeuticuse. 3. Chromium–toxicity. QV290] 615.2532–dc23 2012022691 AcataloguerecordforthisbookisavailablefromtheBritishLibrary. ClothISBN:9780470664827 Typesetin10.5/13ptSabonbyAptaraInc.,NewDelhi,India. iv JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 Contents Preface ix Acknowledgements xiii 1 Introduction–TheCurrentStatusofChromium(III) 1 References 5 2 IsChromiumEssential?TheEvidence 7 2.1 ‘Chromium-Deficient’DietStudieswithRats 9 2.2 TotalParenteralNutrition 11 2.3 ChromiumAbsorptionVersusIntakeandthe TransportofChromiumbyTransferrin 12 2.4 ChromiumMovementRelatedtoStresses 21 References 25 3 TheStoryofGlucoseToleranceFactor(GTF) 31 3.1 The‘Identification’ofGTF 31 3.2 Brewer’sYeast‘GTF’ 35 3.3 BiologicalActivityAssays 39 3.4 PorcineKidneyPowder‘GTF’ 40 3.5 OtherQuestionsRegarding‘GTF’ 40 3.6 ConclusionsaboutGTF 41 3.7 TheRacetoSynthesizeaModelof‘GTF’ 42 3.8 RelatedAnimalStudies 43 References 48 v JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 vi CONTENTS 4 IsChromiumEffectiveasaNutraceutical? 55 4.1 ChromiumPicolinateAbsorption 55 4.2 HistoryofChromiumPicolinateasaNutritional Supplement 57 4.3 ChromiumPicolinateToxicEffects? 73 4.4 InorganicChemistryofChromiumPicolinate 73 References 75 5 IsChromium(III)EffectiveasaTherapeuticAgent? 81 5.1 HumanStudies 85 5.1.1 Type2Diabetes 85 5.1.2 SubjectswithInsulinResistanceorGlucose Intolerance 98 5.1.3 OtherFormsofDiabetes 98 5.1.4 AtypicalDepressionandRelated Conditions 99 5.1.5 HIVandPCOS 101 5.2 RatStudies 102 5.3 Conclusion 114 References 115 6 BiochemicalMechanisms 125 6.1 TheInsulinSignallingPathway 125 6.2 ChromiumTransportandExcretion 127 6.3 LMWCr/Chromodulin 132 6.4 SyntheticModelsofLMWCr 144 6.5 ProposedMechanismsofChromiumAction 149 6.5.1 DirectChromiumBindingtoInsulin Receptor 149 6.5.2 Akt 151 6.5.3 Cholesterol 152 6.5.4 Chromate 152 6.5.5 Cytokines 154 6.5.6 InsulinReceptorNumber 155 6.6 ComparisonofCellCultureStudiesbyCellType 155 6.6.1 SkeletalMuscle 155 6.6.2 Hepatocytes 156 6.6.3 Adipocytes 156 6.7 Conclusion 158 References 159 JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 CONTENTS vii 7 MenagerieofChromiumSupplements 169 7.1 ChromiumPicolinate 169 7.2 ChromiumNicotinate(orChromium Polynicotinate) 170 7.3 ChromiumHistidine 172 7.4 Chromium454 173 7.5 ChromiumNanoparticles 173 7.6 ChromiumSmallPeptideComplexes(CrSP) 174 7.7 Dinakrome 174 7.8 Chromium(D-phenylalanine) 174 3 7.9 ChromiumNicotinateGlycinate(orChromium DinicotinateGlycinate) 175 7.10 ChromiumPidolate 175 7.11 ChromiumMethionineorChromiumMethionine Chelate 176 7.12 Cr3/Kemtrace 176 7.13 ClosingThoughts 179 References 179 8 PotentialUseofChromiumintheFarm LivestockIndustry 189 8.1 PreviousReviews 189 8.2 ApprovedUseofChromium Supplements 191 8.3 Safety 191 8.4 Conclusions 192 References 192 9 ToxicologyofChromium(III) 195 9.1 ChromiumPicolinate 198 9.1.1 AmesAssays 198 9.1.2 CulturedMammalianCells 199 9.1.3 DrosophilaStudies 200 9.1.4 MammalianStudies(Intravenousor Intraperitoneal) 201 9.1.5 MammalianStudies(Oral) 202 9.1.6 NeurologicalEffects 204 9.1.7 InVitroStudies 204 9.1.8 ReconcilingInVitroand InVivoStudies 205 JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 viii CONTENTS 9.2 ChromiumNicotinate 207 9.3 Cr3/Kemtrace 208 9.4 Conclusions 208 References 209 Conclusion 215 Index 217 JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 Preface Two oxidation states of chromium, Cr3+ and Cr6+, are generally con- sideredbiologicallyandenvironmentallyrelevantandstable,thatis,they arestableinthepresenceofairandwater.Chromium(III)complexesare bothkineticallyandthermodynamicallystable.However,chromium(VI) complexesarekineticallystablebutunstablethermodynamically.Inthe presence of appropriate reducing agents, Cr6+ can readily be reduced viaCr4+ and/orCr5+ intermediatesultimatelytoCr3+. The biochemistries of both Cr3+ and Cr6+ have controversial histo- ries. The public is generally more familiar with the chemistry of Cr6+ (or chromate) because of its toxicity. Chromium(VI), d0, is most commonly encountered as the intensely coloured chromate, [CrO ]2−, or 4 dichromate, [Cr O ]2−, anions. These two species are interconvertable 2 7 inwater.ChromateoccursatbasicpHvaluesandhasadistinctiveyellow colour; PbCrO has been used as the pigment in paint used for yellow 4 highway lines. Below pH 6, chromate is in equilibrium with yellow– orange dichromate. Acidic dichromate solutions are potent oxidants. The coordination environment of chromium in both the chromate and dichromate anions is tetrahedral. The intense colour of both anions re- sultsfromligandtometalchargetransferbands.Mixedligandcomplexes of Cr6+ with oxides and halides or oxides and amines are well known, asareCr(VI)peroxocomplexes.ThediamagneticCr6+ centredoesnot give rise to ESR (electron spin resonance) spectra, while NMR (nuclear magnetic resonance) studies of Cr(VI) complexes with oxo, peroxo and haloligandsareoflimitedutility. WhileCr(VI)complexesareknowntobepotentcarcinogensandmu- tagens when inhaled, a serious debate has arisen with regards to the effectsoftheoralintakeofthesecomplexes,asillustratedinrecentyears by the popular movie Erin Brokovich. Chromium(VI) complexes could ix JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 x PREFACE giverisetotheseeffectsthroughanumberofmechanisms,includingox- idationbythecomplexesorthesubsequentlygeneratedCr4+ andCr5+ intermediates, reactions of reactive oxygen species (ROS) generated as by-products of these oxidations, reactions of organic radicals generated in these processes and the binding of the ultimately generated Cr3+ to biomolecules. The relative importance of these mechanisms is far from beingexplained. However,whilethechemistryofCr6+ andCr3+ maybeintertwined to some degree and this intertwining cannot simply be dismissed, this book focuses on the biochemistry of Cr3+, particularly in terms of its potential use as a nutritional supplement, nutraceutical agent or phar- maceutical agent. (The coordination of Cr3+ ions to DNA as a result ofCr6+ reductionisbeyondthescopeofthiswork,andthenatureand significanceofthisbindingisacurrenttopicofmuchdebate.) Coordination complexes of Cr3+ are nearly always octahedral. Con- sequently,thechromiccentrehasad3 electronconfigurationwiththree unpaired electrons (S = 3/2) in each of the t orbitals. This config- 2g uration is responsible for the kinetic inertness of Cr(III) complexes, where ligand exchange half-times are generally in the range of hours. The hexaaquo ion of chromium, [Cr(H O) ]3+, is purple in aqueous 2 6 solution. Solutions of the ion are acidic; at neutral and basic pH the ion readily oligomerizes to give hydroxo-bridged species starting with the [(H O) Cr(μ-OH) Cr(H O) ]4+ ion. The commonly used com- 2 5 2 2 5 mercial form of CrCl .6H O is actually trans-[Cr(H O) Cl ]Cl.2H O. 3 2 2 4 2 2 Dissolution of this green solid initially yields green solutions of the [Cr(H O) Cl ]+ cation. The Cr3+ ion has a large charge to size ra- 2 4 2 tio and is considered as a hard Lewis acid, preferring oxygen and ni- trogen coordination. With common biomolecules, coordination to an- ionic oxygen-based ligands such phosphates and carboxylates would beexpected. The magnetic and spectroscopic properties of chromium(III) complexes do not readily lend themselves to providing much information on the coordination environment of chromic centres in biomolecules. For mononuclear complexes, a magnetic moment close to the spin-only value for an S = 3/2 centre (3.88 BM) is generally observed. While 1H and 13C nuclear magnetic resonance spectra can be obtained on Cr(III) complexes, the spin 3/2 centre results in greatly broadened and shifted resonances in NMR spectra. The structure of the complex must generally be known in order to interpret the NMR spectra, rather than the reverse. In contrast, Cr(III) complexes can give rise to sharp features in ESR spectra (ESR is also known as electron paramagnetic resonance JWST232-fm JBST232-Vincent Printer: YettoCome Trim:229mmX152mm September5,2012 7:50 PREFACE xi (EPR) spectroscopy); however, the ESR spectra of biomolecules have often proved to be quite broad, providing limited information. ESR spectroscopyisprobablyasignificantlyunderutilizedtechniqueinchar- acterising chromium in biological systems. Cr3+ as an impurity in the Al O matrix of emeralds and rubies gives rise to the green and red 2 3 colourofthesegems;yet,theelectronicspectraofchromium-containing biomolecules are usually very simple. Three spin-allowed d→d transi- tions are expected; two usually occur in the visible region, while the thirdisexpectedintheultravioletregion(whereitcanbehiddenbylig- andbasedfeatures).Nochargetransfertransitionsgenerallyoccurwhile thevisibleabsorptionbandshaveextinctioncoefficientsoftypicallyless than 100 M−1 cm−1. Thus, only relatively concentrated solutions of Cr3+ have appreciably observable colour. Cr(III) complexes are gener- allystableagainstoxidationorreduction. Although chromium as theCr3+ ionwas proposed to beanessential element about 50 years ago, its status is currently in question, as recent experiments appear to demonstrate that the element can no longer be considered essential. Supplemental nutritional doses of Cr3+ have been proposed to result in body mass loss and lean muscle mass development, leading to an appreciable nutraceutical industry being built aroundchromium.However,theseclaimshavebeenthoroughlyrefuted. Chromiumhasalsobeensuggestedtobeaconditionallyessentialelement whosesupplementationcouldleadtoimprovementsincarbohydrateand lipidmetabolismundercertainstresssituations,includingtype2diabetes and the effects of shipment of farm animals; this is currently an area of intense and hotly debated research with recent findings suggesting that beneficialeffectsfromCr3+ supplementationarepharmacologically,not nutritionally,relevant.Atthesametime,supplementationofthedietwith at least certain Cr(III) complexes has been proposed to have potentially deleteriouseffects. Chapter1examinesthecurrentstatusofchromiumasdefinedbyvar- ious government agencies or public foundations. Chapter 2 reviews the evidencethatchromiumisanessentialtraceelement.Chapter3explores thehistoryofnutritionalstudiesonchromium(III)complexes.Theability of chromium(III) complex supplementation to generate body composi- tion changes is covered in Chapter 4, while potential pharmacological effects of chromium supplementation, particularly for type 2 diabetic subjects, is reviewed in Chapter 5. Chapter 6 explores the mechanisms bywhichchromiummighthavepharmacologicaleffects.Chapters7and 8 review chromium supplements that are commercially available or un- der development and the use of chromium supplements in farm animal