The bioinorganic chemistry of chromium

JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 The Bioinorganic Chemistry of Chromium i JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm September 5, 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: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 This edition first published 2013 C 2013 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book This publication is designed to provide accurate and authoritative information in regard to the subject matter covered It is sold on the understanding that the publisher is not engaged in rendering professional services If professional advice or other expert assistance is required, the services of a competent professional should be sought The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose This work is sold with the understanding that the publisher is not engaged in rendering professional services The advice and strategies contained herein may not be suitable for every situation In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging-in-Publication Data Vincent, John B (John Bertram) The bioinorganic chemistry of chromium / John B Vincent p ; cm Includes bibliographical references and index ISBN 978-0-470-66482-7 (cloth) I Title [DNLM: Chromium–chemistry Chromium–therapeutic use Chromium–toxicity QV 290] 615.2532–dc23 2012022691 A catalogue record for this book is available from the British Library Cloth ISBN: 9780470664827 Typeset in 10.5/13pt Sabon by Aptara Inc., New Delhi, India iv JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 Contents Preface ix Acknowledgements xiii Introduction – The Current Status of Chromium(III) References Is Chromium Essential? The Evidence 2.1 ‘Chromium-Deficient’ Diet Studies with Rats 2.2 Total Parenteral Nutrition 2.3 Chromium Absorption Versus Intake and the Transport of Chromium by Transferrin 2.4 Chromium Movement Related to Stresses References 12 21 25 The Story of Glucose Tolerance Factor (GTF) 3.1 The ‘Identification’ of GTF 3.2 Brewer’s Yeast ‘GTF’ 3.3 Biological Activity Assays 3.4 Porcine Kidney Powder ‘GTF’ 3.5 Other Questions Regarding ‘GTF’ 3.6 Conclusions about GTF 3.7 The Race to Synthesize a Model of ‘GTF’ 3.8 Related Animal Studies References 31 31 35 39 40 40 41 42 43 48 v 11 JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm vi September 5, 2012 7:50 CONTENTS Is Chromium Effective as a Nutraceutical? 4.1 Chromium Picolinate Absorption 4.2 History of Chromium Picolinate as a Nutritional Supplement 4.3 Chromium Picolinate Toxic Effects? 4.4 Inorganic Chemistry of Chromium Picolinate References Is Chromium(III) Effective as a Therapeutic Agent? 5.1 Human Studies 5.1.1 Type Diabetes 5.1.2 Subjects with Insulin Resistance or Glucose Intolerance 5.1.3 Other Forms of Diabetes 5.1.4 Atypical Depression and Related Conditions 5.1.5 HIV and PCOS 5.2 Rat Studies 5.3 Conclusion References Biochemical Mechanisms 6.1 The Insulin Signalling Pathway 6.2 Chromium Transport and Excretion 6.3 LMWCr/Chromodulin 6.4 Synthetic Models of LMWCr 6.5 Proposed Mechanisms of Chromium Action 6.5.1 Direct Chromium Binding to Insulin Receptor 6.5.2 Akt 6.5.3 Cholesterol 6.5.4 Chromate 6.5.5 Cytokines 6.5.6 Insulin Receptor Number 6.6 Comparison of Cell Culture Studies by Cell Type 6.6.1 Skeletal Muscle 6.6.2 Hepatocytes 6.6.3 Adipocytes 6.7 Conclusion References 55 55 57 73 73 75 81 85 85 98 98 99 101 102 114 115 125 125 127 132 144 149 149 151 152 152 154 155 155 155 156 156 158 159 JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm CONTENTS Menagerie of Chromium Supplements 7.1 Chromium Picolinate 7.2 Chromium Nicotinate (or Chromium Polynicotinate) 7.3 Chromium Histidine 7.4 Chromium454 7.5 Chromium Nanoparticles 7.6 Chromium Small Peptide Complexes (CrSP) 7.7 Dinakrome 7.8 Chromium(D-phenylalanine)3 7.9 Chromium Nicotinate Glycinate (or Chromium Dinicotinate Glycinate) 7.10 Chromium Pidolate 7.11 Chromium Methionine or Chromium Methionine Chelate 7.12 Cr3/Kemtrace 7.13 Closing Thoughts References Potential Use of Chromium in the Farm Livestock Industry 8.1 Previous Reviews 8.2 Approved Use of Chromium Supplements 8.3 Safety 8.4 Conclusions References Toxicology of Chromium(III) 9.1 Chromium Picolinate 9.1.1 Ames Assays 9.1.2 Cultured Mammalian Cells 9.1.3 Drosophila Studies 9.1.4 Mammalian Studies (Intravenous or Intraperitoneal) 9.1.5 Mammalian Studies (Oral) 9.1.6 Neurological Effects 9.1.7 In Vitro Studies 9.1.8 Reconciling In Vitro and In Vivo Studies September 5, 2012 7:50 vii 169 169 170 172 173 173 174 174 174 175 175 176 176 179 179 189 189 191 191 192 192 195 198 198 199 200 201 202 204 204 205 JWST232-fm JBST232-Vincent Printer: Yet to Come viii Trim: 229mm X 152mm September 5, 2012 7:50 CONTENTS 9.2 Chromium Nicotinate 9.3 Cr3/Kemtrace 9.4 Conclusions References 207 208 208 209 Conclusion 215 Index 217 JWST232-fm JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 Preface Two oxidation states of chromium, Cr3 + and Cr6 + , are generally considered biologically and environmentally relevant and stable, that is, they are stable in the presence of air and water Chromium(III) complexes are both kinetically and thermodynamically stable However, chromium(VI) complexes are kinetically stable but unstable thermodynamically In the presence of appropriate reducing agents, Cr6 + can readily be reduced via Cr4 + and/or Cr5 + intermediates ultimately to Cr3 + The biochemistries of both Cr3 + and Cr6 + have controversial histories 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, [CrO4 ]2− , or dichromate, [Cr2 O7 ]2− , anions These two species are interconvertable in water Chromate occurs at basic pH values and has a distinctive yellow colour; PbCrO4 has been used as the pigment in paint used for yellow 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 results from ligand to metal charge transfer bands Mixed ligand complexes of Cr6 + with oxides and halides or oxides and amines are well known, as are Cr(VI) peroxo complexes The diamagnetic Cr6 + centre does not give rise to ESR (electron spin resonance) spectra, while NMR (nuclear magnetic resonance) studies of Cr(VI) complexes with oxo, peroxo and halo ligands are of limited utility While Cr(VI) complexes are known to be potent carcinogens and mutagens when inhaled, a serious debate has arisen with regards to the effects of the oral intake of these complexes, as illustrated in recent years by the popular movie Erin Brokovich Chromium(VI) complexes could ix JWST232-fm JBST232-Vincent x Printer: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 PREFACE give rise to these effects through a number of mechanisms, including oxidation by the complexes or the subsequently generated Cr4 + and Cr5 + 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 being explained However, while the chemistry of Cr6 + and Cr3 + may be intertwined 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 pharmaceutical agent (The coordination of Cr3 + ions to DNA as a result of Cr6 + reduction is beyond the scope of this work, and the nature and significance of this binding is a current topic of much debate.) Coordination complexes of Cr3 + are nearly always octahedral Consequently, the chromic centre has a d3 electron configuration with three unpaired electrons (S = 3/2) in each of the t2g orbitals This configuration 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(H2 O)6 ]3 + , is purple in aqueous solution Solutions of the ion are acidic; at neutral and basic pH the ion readily oligomerizes to give hydroxo-bridged species starting with the [(H2 O)5 Cr(μ-OH)2 Cr(H2 O)5 ]4 + ion The commonly used commercial form of CrCl3 6H2 O is actually trans-[Cr(H2 O)4 Cl2 ]Cl 2H2 O Dissolution of this green solid initially yields green solutions of the [Cr(H2 O)4 Cl2 ] + cation The Cr3 + ion has a large charge to size ratio and is considered as a hard Lewis acid, preferring oxygen and nitrogen coordination With common biomolecules, coordination to anionic oxygen-based ligands such phosphates and carboxylates would be expected The magnetic and spectroscopic properties of chromium(III) complexes 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 H and 13 C 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 PREFACE Printer: Yet to Come Trim: 229mm X 152mm September 5, 2012 7:50 xi (EPR) spectroscopy); however, the ESR spectra of biomolecules have often proved to be quite broad, providing limited information ESR spectroscopy is probably a significantly underutilized technique in characterising chromium in biological systems Cr3 + as an impurity in the Al2 O3 matrix of emeralds and rubies gives rise to the green and red colour of these gems; yet, the electronic spectra of chromium-containing biomolecules are usually very simple Three spin-allowed d→d transitions are expected; two usually occur in the visible region, while the third is expected in the ultraviolet region (where it can be hidden by ligand based features) No charge transfer transitions generally occur while the visible absorption bands have extinction coefficients of typically less than 100 M−1 cm−1 Thus, only relatively concentrated solutions of Cr3 + have appreciably observable colour Cr(III) complexes are generally stable against oxidation or reduction Although chromium as the Cr3 + ion was proposed to be an essential 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 around chromium However, these claims have been thoroughly refuted Chromium has also been suggested to be a conditionally essential element whose supplementation could lead to improvements in carbohydrate and lipid metabolism under certain stress situations, including type diabetes and the effects of shipment of farm animals; this is currently an area of intense and hotly debated research with recent findings suggesting that beneficial effects from Cr3 + supplementation are pharmacologically, not nutritionally, relevant At the same time, supplementation of the diet with at least certain Cr(III) complexes has been proposed to have potentially deleterious effects Chapter examines the current status of chromium as defined by various government agencies or public foundations Chapter reviews the evidence that chromium is an essential trace element Chapter explores the history of nutritional studies on chromium(III) complexes The ability of chromium(III) complex supplementation to generate body composition changes is covered in Chapter 4, while potential pharmacological effects of chromium supplementation, particularly for type diabetic subjects, is reviewed in Chapter Chapter explores the mechanisms by which chromium might have pharmacological effects Chapters and review chromium supplements that are commercially available or under development and the use of chromium supplements in farm animal JWST232-c09 210 JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm THE BIOINORGANIC CHEMISTRY OF CHROMIUM 12 Stearns, D.M., Wise Sr., J.P., Patierno, S.R and Wetterhahn, K.E (1995) Chromium(III) picolinate produces chromosome damage in Chinese hamster ovary cells FASEB J., 9, 1643–1648 13 Gudi, R., Slesinski, R.S., Clarke, J.J and Sans, R.H.C (2005) Chromium picolinate does not produce chromosome damage in CHO cells Mutat Res., 587, 140–146 14 Bagchi, D., Stohs, S.J., Downs, B.W et al (2002) Cytotoxicity and oxidative mechanisms of different forms of chromium Toxicology, 180, 5–22 15 Stearns, D.M., Silveira, S.M, Wolf, K.K and Lake, A.M (2002) Chromium(III) tris(picolinate) is mutagenic at the hypoxanthine (guanine) phopshoribosyl transferase locus in Chinese hamster ovary cells Mutat Res., 513, 135–142 16 Hininger, I., Benarba, R., Osman, M et al (2007) Safety of trivalent chromium complexes: no evidence for DNA damage in human HaCaT keratinocytes Free Radic Biol Med., 42, 1759–1765 17 Manygoats, K.R., Yazzie, M and Stearns, D.M (2002) Ultrastructural damage in chromium picolinate-treated cells: a TEM study J Biol Inorg Chem., 7, 791–798 18 Coryell, V.H and Stearns, D.M (2006) Molecular analysis of hprt mutations induced by chromium picolinate in CHO AA8 cells Mutat Res., 610, 114–223 19 Jana, M., Rajaram, A and Rajaram, R (2009) Chromium picolinate induced apoptosis of lymphocytes and the signaling mechanisms thereof Toxicol Appl Pharmacol., 237, 331–344 20 Jana, M., Rajaram, A and Rajaram, R (2010) Autoschizis of T-cells is induced by the nutritional supplement Cr(III)picolinate Toxicol In Vitro, 24, 586–596 21 Andersson, M.A., Grawe, K.V.P., Karlsson, O.M et al (2007) Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro Food Chem Toxicol., 45, 1097–1106 22 Shrivastava, H.Y., Ravikumar, T., Shanmugasundaram, N et al (2005) Cytotoxicity studies of chromium(III) complexes on human dermal fibroblasts Free Radic Biol Med., 38, 58–69 23 Witmer, C, Faria, E, Park, H.-S et al (1994) In vivo effects of chromium Environ Health Perspect., 102 (Suppl 3), 169–176 24 Hepburn, D.D.D., Xiao, J., Bindom, S et al (2003) Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster Proc Natl Acad Sci., USA, 100, 3766–3771 25 Stallings, D.M., Hepburn, D.D., Hannah, M et al (2006) Nutritional supplement chromium picolinate generates chromosomal aberrations and impedes progeny development in Drosophila melanogaster Mutat Res., 610, 101–113 26 Hepburn, D.D.D., Burney, J., Woski, S.A and Vincent, J.B (2003) The nutritional supplement chromium picolinate generates oxidative DNA damage and peroxidized lipids in vivo Polyhedron, 22, 455–463 27 Preuss, H.G., Grojec, P.L., Lieberman, S and Anderson, R.A (1997) Effects of different chromium compounds on blood pressure and peroxidation in spontaneously hypertensive rats Clin Nephrol., 47, 325–330 28 Rhodes, M.C., Hebert, C.D., Herbert, R.A et al (2005) Absence of toxic effect in F344/N rats and B6C3F1 mice following subchronic administration of chromium picolinate monohydrate Food Chem Toxicol., 43, 21–29 29 Anderson, R.A., Bryden, N.A and Polansky, M.M (1997) Lack of toxicity of chromium chloride and chromium picolinate in rats J Am Coll Nutr., 16, 273–279 August 4, 2012 10:0 JWST232-c09 JBST232-Vincent Printer: Yet to Come TOXICOLOGY OF CHROMIUM(III) Trim: 229mm X 152mm August 4, 2012 10:0 211 30 Bailey, M.M., Boohaker, J.G., Sawyer, R.D et al (2006) Exposure of pregnant mice to chromium picolinate results in skeletal defects in their offspring Birth Defect Res B, 77, 244–249 31 Komorowski, J.R., Greenberg, D and Juturu, V (2008) Chromium picolinate does not produce chromosome damage Toxicol In Vitro, 22, 819–826 32 Kato, I., Vogelman, J.H., Dilman, V et al (1998) Effect of supplementation with chromium picolinate on antibody titers to 5-hydroxymethyl uracil Eur J Epidemology, 14, 621–626 33 Mozaffari, M.S., Abdelsayed, R., Liu, J.Y et al (2009) Effects of chromium picolinate on glycemic control and kidney of the obese Zucker rat Nutr Metabol., 6, doi: 10.1186/1743-7075-6-61 34 Stout, M.D., Nyska, A., Collins, B.J et al (2009) Chronic toxicity and carcinogenicity studies of chromium picolinate monohydrate administered in feed to F344/N rats and B6C3F1 mice for years Food Chem Toxicol., 47, 729–733 35 Bailey, M.M., Sturdivant, J., Jernigan, P.L et al (2008) Comparison of the potential for developmental toxicity of prenatal exposure to two dietary chromium supplements, chromium picolinate and [Cr3 O(O2 CCH2 CH3 )6 (H2 O)3 ] + , in mice Birth Defect Res B, 83, 27–31 36 Bailey, M.M., Boohaker, J.G., Jernigan, P.L et al (2008) Effects of pre- and postnatal exposure to chromium picolinate or picolinic acid on neurological development in CD-1 mice Biol Trace Elem Res., 124, 70–82 37 Mahmoud, A.A., Karam, S.H and Abdel-Wahhab, M.A (2006) Chromiumpicolinate induced ocular changes: protective role of ascorbic acid Toxicology, 226, 143–151 38 Berkeley Wellness Letter Wellness Guide to Dietary Supplements: Chromium http://www.berkeley.com/html/ds/dsChromium.php (accessed 10 April 2006) 39 Stearns, D.M (2007) Evaluation of chromium(III) genotoxicity with cell culture and in vitro assays, in The Nutritional Biochemistry of Chromium(III) (ed J.B Vincent), Elsevier, Amsterdam, pp 209–224 40 Jeffcoat, A.R (2002) [14 C]Chromium Picolinate Monohydrate: Disposition and Metabolism in Rats and Mice, submitted to National Institutes of Environmental Health Sciences Research Triangle Institute, Project Report http://www.rti.org/ publications/abstract.cfm?pubid=17856 (accessed 28 June 2012) 41 Sugden, K.D., Geer, R.D and Rogers, S.G (1992) Oxygen radical-mediated DNA damage by redox-active Cr(III) complexes Biochemistry, 31, 11626–11631 42 Ringden, D., Lee, S.H., Nakajima, M and Blair, I.A (2000) Formation of a substituted 1,N6 -etheno-2 -deoxyadenosine adduct by lipid hydroperoxide-mediated generation of 4-oxo-2-nonenal Chem Res Toxicol., 13, 846–852 43 Tan, G.-Y., Zheng, S.-S., Zhang, M.-H et al (2008) Study of oxidative damage in growing-finishing pigs with continuous excess dietary chromium picolinate intake Biol Trace Elem Res., 126, 129–140 44 McAdory, D., Rhodes, N.R., Briggins, F et al (2011) Potential of chromium(III) picolinate for reproductive or developmental toxicity following exposure of male CD-1 mice prior to mating Biol Trace Elem Res., 143, 1666–1672 45 Cerulli, J., Grabe, D.W., Gauthier, I et al (1998) Chromium picolinate toxicity Ann Pharmacother., 32, 428–431 46 Wasser, W.G and D’Agati, V.D (1997) Chromic renal failure after ingestion of overthe-counter chromium picolinate Ann Int Med., 126, 410 To follow the debate over JWST232-c09 JBST232-Vincent 212 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 Printer: Yet to Come Trim: 229mm X 152mm THE BIOINORGANIC CHEMISTRY OF CHROMIUM this article see also the following letters to the editor: McCarty, M.F (1997) To the editor Ann Int Med., 127, 654–655; Hathcock, J.N (1997) To the editor Ann Int Med., 127, 655; Michenfelder, H.J., Thompson, J and Shepherd, M (1997) To the editor Ann Int Med., 127, 655; Mennen, B (1997) To the editor Ann Int Med., 127, 655–656; and Wasser, W.G and D’Agati, V.D (1997) In response Ann Int Med., 127, 656 Martin, W.R and Fuller, R.E (1998) Suspected chromium picolinate-induced rhabdomyolysis Pharmacotherapy, 18, 860–862 Fowler Jr., J.F (2000) Systemic contact dermatitis caused by oral chromium picolinate Cutis, 65, 116 Huszonek, J (1993) Over-the-counter chromium picolinate Am J Pyschiatry, 150, 1560–1561 Young, P.C., Turiansky, G.W., Bonner, M.W and Benson, P.M (1999) Acute generalized exanthematous postulosis induced by chromium picolinate J Am Acad Dermatol., 41, 820–823 Bunner, S.P and McGinnis, R (1998) Chromium-induced hypoglycemia Psychosomatics, 39, 298–299 McLeod, M.N., Gaynes, B.N and Golden, R.N (1999) Chromium potentiation of antidepressant pharmocotherapy for dysthymic disorder in patients J Clin Psychiatry, 60, 237–240 McLeod, M.N and Golden, R.N (2000) Chromium treatment of depression Int J Neuropsychopharmacol., 3, 311–314 Attenburrow, M.-J., Odontiadis, J., Murray, B.J et al (2002) Chromium treatment decreases the sensitivity of 5-HT2A receptors Psychopharmacology, 159, 432–436 Mehler, A.H (1956) Formation of picolinic acid and quinolinic acids following enzymatic oxidation of 3-hydroxyanthranilic acid J Biol Chem., 218, 241–253 Boegman, R.J., Jhamandas, K., Beninger, R.J (1990) Neurotoxicity of tryptophan metabolites Ann N Y Acad Sci., 585, 261–273 Kareus, S.A., Kelley, C., Walton, H.S and Sinclair, P.R (2001) Release of Cr(III) from Cr(III) picolinate upon metabolic activation J Hazardous Mat., B84, 163–174 Imamoglu, N., Uyamk, F., Guclu, B.K et al (2008) Effects of chromium picolinate on micronucleus frequency and morphology of lymphocytes in calves Biol Trace Elem Res., 125, 133–140 Al-Qutati, A., Winter, P.W, Wolf-Ringwall, A.L et al (2012) Insulin receptors and downstream substrates associate with membrane microdomains after treatment with insulin or chromium(III) picolinate Cell Biochem Biophys., 62, 441–450 Evans, G.W and Bowman, T.D (1992) Chromium picolinate increases membrane fluidity and rate of insulin internalization J Inorg Biochem., 46, 243–250 Shara, M., Yasmin, T., Kincaid, A.E et al (2005) Safety and toxicological evaluation of a novel niacin-bound chromium (III) complex J Inorg Biochem., 99, 2161–2183 Shara, M., Kincaid, A.E., Limpach, A.L et al (2007) Long-term safety evaluation of a novel oxygen-coordinated niacin-bound chromium (III) complex J Inorg Biochem., 101, 1059–1069 Deshmukh, N.S., Bagchi, M., Lau, F.C and Bagchi, D (2009) Safety of a novel oxygen-coordinated niacin-bound chromium(III) complex (NBC): I Two-generation reproduction toxicity study J Inorg Biochem., 103, 1748–1754 August 4, 2012 10:0 JWST232-c09 JBST232-Vincent Printer: Yet to Come TOXICOLOGY OF CHROMIUM(III) Trim: 229mm X 152mm August 4, 2012 10:0 213 64 Deshmukh, N.S, Bagchi, M., Lau, F.C and Bagchi, D (2009) Safety of an oxygencoordinated niacin-bound chromium(III) complex (NBC): II Developmental toxicity study in rats J Inorg Biochem., 103, 1755–1760 65 Staniek, H., Krejpcio, Z and Iwanik, K (2010) Evaluation of the acute oral toxicity class of tricentric chromium(III) propionate complex in rat Food Chem Toxicol., 48, 859–864 66 Staniek, H., Kostrzewska-Poczekaj, M., Arndt, M et al (2010) Genotoxicity assessment of chromium(III) propionate complex in the rat model using the comet assay Food Chem Toxicol., 48, 89–92 67 Bennett, R., Adams, B., French, A et al (2006) High-dose chromium(III) supplementation has no effects on body mass and composition while altering plasma hormone and triglycerides concentrations Biol Trace Elem Res., 113, 53–66 68 Staniek, H and Krejpcio, K (2009) The effects of tricentric chromium(III) propionate complex supplementation on pregnancy outcome and maternal and foetal mineral status in rat Food Chem Toxicol., 47, 2673–2678 69 Clodfelder, B.J., Gullick, B.M., Lukaski, H.C et al (2005) Oral administration of the biomimetic [Cr3 O(O2 CCH2 CH3 )6 (H2 O)3 ] + increases insulin sensitivity and improves blood variables in healthy and type diabetic rats J Biol Inorg Chem., 10, 119–130 70 Parand, A., Royer, A.C., Cantrell, T.L et al (1998) DNA by a trinuclear chromium complex Inorg Chim Acta, 268, 211–219 71 Speetjens, J.K., Parand, A., Crowder, M.W et al (1999) Low-molecular-weight chromium-binding substance and biomimetic [Cr3 O(O2 CCH2 CH3 )6 (H2 O)3 ] + not cleave DNA under physiologically relevant conditions Polyhedron, 18, 2617–2624 JWST232-Conc JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm Conclusion This review of the literature on the biochemistry of chromium(III) lends itself to several conclusions: (1) At present chromium cannot be considered as an essential element as (i) nutritional data demonstrating chromium deficiency and improvement in symptoms from chromium supplementation are lacking and (ii) no biomolecules have convincingly been demonstrated to bind chromium and have an essential function in the body The next review of the status of chromium by the Committee on the Scientific Evaluation of Dietary Reference Intakes of the National Academies of Science (USA) must seriously consider revising its status (2) The Federal Trade Commission (USA) in 1997 properly stopped claims of body mass loss and changes in body composition from chromium picolinate supplementation as subsequent research has verified that chromium supplementation does not affect body mass or body composition No beneficial effects have been demonstrated from chromium supplementation by healthy individuals (3) The American Diabetes Association position to not recommend chromium(III) supplementation for people with type diabetes or obesity is appropriate given the scientific literature that lacks consistent and reproducible outcomes Future studies need to be more carefully designed including in terms of number of subjects and amount of chromium being utilized; to use well characterized The Bioinorganic Chemistry of Chromium, First Edition John B Vincent C 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd 215 September 5, 2012 12:2 JWST232-Conc JBST232-Vincent 216 Printer: Yet to Come Trim: 229mm X 152mm CONCLUSION chromium(III) compounds; and to examine whether particular subgroups of type diabetic subjects are likely to benefit from chromium supplementation (4) No molecular level mechanism has been clearly established for explaining how chromium could have a beneficial role in carbohydrate and lipid metabolism Similarly, key details in the transportation, distribution and elimination of chromium(III) from the body at a molecular level are lacking To address this situation, inorganic chemists, biochemists, nutritionists and medical researchers need to have greater collaboration when designing and performing experiments For example, an understanding of exactly what form of chromium the cultured cells are exposed to in experiments is crucial to trying to reconcile the conflicting results on the effects of chromium on the insulin signalling cascade Progress in understanding how chromium could potentially influence carbohydrate and lipid metabolism and using this information to possibly influence the health of humans and animals will not occur until the heterogeneity of results can be reconciled Recent studies on LMWCr may be a start to finally elucidating the mechanism of chromium action in enhancing insulin sensitivity (5) Chromium(III) supplementation appears to be safe at levels currently used in nutritional supplements and in pharmacology studies, in line with assessments by the Food and Drug Administration (USA) and European Food Safety Authority However, as no benefit has been demonstrated for chromium supplementation of healthy individuals, any potential risk from supplementation would appear to outweigh potential benefits Risk benefit analysis is more difficult for animals under stress (including type diabetics) Further research is required before proper assessment of the potential risks versus benefits of chromium supplementation can be performed in these cases Future clinical trials may require the use of larger doses of chromium(III); these trials will require careful monitoring of possible deleterious effects from supplementation September 5, 2012 12:2 JWST232-bind JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm Index apolipoprotein B 58 apoptosis 199–200 apoptotic cells 206 ascorbate 205 ascorbic acid 14, 86, 208 athletes 23, 58, 71–2 autoschizis 200 AvilaCr 176 3T3-L1 adipocytes 149, 151, 152, 156–7 4E-BP1 151, 157 A549 cells 200 acute phase response 178 ADAM 19 134 adequate intake (AI) 2, 169 adipocytes 3T3-L1 149, 151, 152, 156–7 and Brewer’s yeast GTF 38–41 cell culture studies 156–8 insulin dose response studies 136–7 ageing 131 AI see adequate intake AIN-93G diet 10 Akt (protein kinase B) 127, 144, 149, 151–3, 156–7, 207 Albion 175 albumin 18, 149 see also conalbumin alloxan 84, 113 American alligator 143, 144 American Diabetes Association 3, 215 Ames assays 198–9, 206, 207 amino acids and absorption of chromium 14, 17 and Brewer’s yeast GTF 35, 36–7, 41 composition of LMWCr 133–4, 142 anaemia 204 animal feed supplements 4, 176, 178, 191–2 apolipoprotein 58 apolipoprotein A1 58, 156 BCI index see body composition improvement (BCI) index bile 131 biological activity assays 38, 39–40 biotin 91, 169 bipolar disorder 99 blood pressure 71, 90, 91, 92 body composition 48, 59–72, 215 body composition improvement (BCI) index 66, 68 body fat 4, 58, 63, 65–71, 91, 92 body mass 192, 215 and biomimetic for LMWCr 145 and chromium histidine 113 and chromium nanoparticles 174 and chromium nicotinate 207 and chromium picolinate 2, 59–63, 65, 67–73, 91–3, 102–3, 110, 112–13, 202 and chromium pidolate 176 and Cr3 110, 208 and CRC454 173 and CrCl3 112, 113 and Cr(D-phenylalanine)3 112 The Bioinorganic Chemistry of Chromium, First Edition John B Vincent C 2013 John Wiley & Sons, Ltd Published 2013 by John Wiley & Sons, Ltd 217 August 17, 2012 11:43 JWST232-bind JBST232-Vincent Printer: Yet to Come 218 body mass (Continued ) and Cr yeast 92 see also lean body mass body mass index 69, 90, 91, 92 body weight 72 bone 131 bone marrow cells 203 bovine colostrum 136 bovine liver 133, 134–5, 137, 143 Brewer’s yeast 86, 87, 96 and glucose tolerance factor 31–3, 35–40, 42 see also chromium-enhanced yeast; chromium yeast C2C12 cells 144, 151, 155–6 caffeine 67 calmodulin 138 calves 206 see also cattle Canada 191 Canadian Food Inspection Agency 191 cancer 177 carbon dioxide 41, 136 carboxylic acid 178 carcinogenicity 4, 157 cardiovascular disease 3, 82–3, 151 L-carnitine 63 catalase 203 cattle 4, 176, 178, 190, 191 see also bovine colostrum; bovine liver; calves; cows’ milk CDNC see chromium dinicocysteinate cell culture studies 155–8, 174 toxicology of chromium picolinate 199–200 ceruloplasmin 13 cervical arch defects 203 Chelex-100 156 chicken liver 143 Chinese hamster ovary (CHO) cells 73, 149, 157, 171, 199 CHO cells see Chinese hamster ovary (CHO) cells cholesterol 86, 93, 111 and biomimetic for LMWCr 145, 146, 147 and Brewer’s yeast 86, 87 and chromium acetate 45–7 and chromium nicotinate 88, 101, 111 and chromium picolinate 58, 63, 71, 87–91, 93, 102, 110, 113, 151, 152, 157 Trim: 229mm X 152mm INDEX and chromium pidolate 89, 176 and chromium-spirula 90 and Cr3 110 and CrCl3 86, 87, 113, 152, 156, 157 and Cr(D-phenylalanine)3 , 112 and Cr yeast 90, 92 and mechanism of action of chromium 152 rats with elevated levels of 102–10 see also high-cholesterol diet; high-density lipoprotein (HDL) cholesterol; low-density liporotein (LDL) cholesterol; very low-density liporotein (VLDL) cholesterol cholesterol homeostasis 152 chromate ix, 86, 132, 133, 136, 140 and mechanism of action of chromium 152–4 Chromax 169 ChromeMate 171, 172 chromic acetate 45, 46, 47, 73 chromic chloride 34, 73 chromic nitrate 73 chromic perchlorate 73 chromic sulfide 73 chromium ix–x absorption 12–17, 83–5 adequate intake (AI) 2, 169 antioxidant effects 90, 92 as an essential element 2–3, 7–25, 215 content in diets 2, 85 current status 1–4 distribution 84, 131 foods rich in general public perception of intake 2, 15–17 levels in tissues 7–8 mechanisms of action 149–55 movement related to stresses 21–5 transport 18–20, 127–31, 140 chromium(III) dinicotinate cysteinate 172 Chromium454 173 chromium acetate 45, 46 Chromium Chelavite 175 chromium chloride (CrCl3 ) absorption and transport 13–14, 18, 57 accumulation and excretion 14–15 and adipocyte cell culture studies 156–8 and body mass 112, 113 and cholesterol 86, 87, 113, 152, 156, 157 August 17, 2012 11:43 JWST232-bind JBST232-Vincent Printer: Yet to Come INDEX and cytokine TNF-␣ 154–5 and glucose levels 86, 87, 89, 91, 113 and glucose removal rates 45 and glucose uptake 149, 156 and glycated haemoglobin 91 and HDL cholesterol 86, 87, 89 and hepatocyte cell culture studies 156 and insulin levels 9, 87, 91, 113 and insulin receptor kinase 150 and insulin resistance 91 and LDL cholesterol 87 and mRNA levels of insulin receptor 149, 156, 174 and skeletal muscle cell culture studies 156 and triglycerides 87, 89, 113 as therapeutic agent 59, 86–7, 89, 91, 93, 110, 112–14, 152, 156–7 effects on 3T3-L1 cells 151, 152, 156 effects on C2C12 cells 151, 156 inhalation exposure 132 solubility 148 use as supplement 57 use in studies 179 chromium deficiency 10, 11, 22, 43–4, 48 and stress 189 in farm animals 191, 192 chromium-deficient diet 8–11, 24, 42 see also chromium-restricted diet; low-chromium diet chromium-deficient rats 39, 45 chromium dinicocysteinate (CDNC) 110, 172 chromium dinicotinate glycinate see chromium nicotinate glycinate chromium-enhanced yeast 44, 67, 90, 190 see also Brewer’s yeast; chromium yeast chromium histidinate 151, 172 chromium histidine 113, 149–51, 157, 172–3 chromium homoeostasis 16–17 Chromium Information Bureau 195 chromium methionine 176 as animal feed supplement 190, 191 chromium methionine chelate 176 chromium nanoparticles 173–4 chromium nicotinate 43, 190 absorption 57 as chromium supplement 170–2 as therapeutic agent 88, 96, 101, 110, 111 solubility 148 toxicology 172, 207–8 chromium nicotinate glycinate 175 Trim: 229mm X 152mm August 17, 2012 11:43 219 chromium picolinate (Cr(pic)3 ) 169–70, 179 absorption 55–7, 158 accumulation and excretion 14–15 and adipocyte cell culture studies 156–8 and Akt phosphorylation 151 and body composition 59–72, 215 and body fat 4, 58, 63, 65–71, 91, 92 and body mass 2, 59–63, 65, 67–73, 91–3, 102–3, 110, 112–13, 202 and cholesterol 58, 63, 71, 87–91, 93, 102, 110, 113, 151, 152, 157 and DNA damage 200–7 and food intake 2, 70, 71, 100, 102, 110, 202 and glucose levels 88, 89, 90, 92, 93, 98, 101, 102, 110, 112, 113 and glucose tolerance tests (GTT) 93, 110, 112, 113 and glucose uptake 149, 152, 157 and glycated haemoglobin 59, 87–93, 96, 110, 111 and HDL cholesterol 87, 88, 89, 91, 93, 101, 110, 152 and insulin levels 70–1, 88–90, 93, 98, 101, 102, 110, 112, 113, 151 and insulin resistance 3, 89 and LDL cholesterol 58, 88, 89, 91, 93, 101, 110 and lean body mass 59, 63, 64, 65, 67, 69 and mRNA levels of insulin receptor 149, 156, 174 and pregnancy 203 and skeletal muscle cell culture studies 156 and triglycerides 70–1, 88, 89, 93, 98, 101, 102, 110, 113 and type diabetes 3–4 as animal feed supplement 191 as nutritional supplement 57–73 as therapeutic agent 86–93, 96–102, 110, 112, 113 current status of 1–2, 3–4 deleterious effects of 204 effects on 3T3-L1 adipocytes 152 inorganic chemistry of 73–5 intraperitoneal administration 202 intravenous administration 201–2, 206 neurological effects 204 oral administration 202–4, 206 oxidation to chromate 153 solubility 148 toxicology 4, 73, 157, 195–207 chromium pidolate 89, 175–6 JWST232-bind JBST232-Vincent Printer: Yet to Come 220 chromium polynicotinate see chromium nicotyniate chromium propionate 178 as animal feed supplement 190, 191 chromium-restricted diet 23 chromium small peptide complexes (CrSP) 174 chromium-spirula 90 chromium supplements 169–79 for farm livestock 4, 176, 178, 189–92 chromium yeast 89, 90, 92, 97, 174, 176, 191 see also Brewer’s yeast; chromium-enhanced yeast chromodulin see low-molecular-weight chromium-binding substance (LMWCr) chromosomal aberrations 199, 200, 201 CID see collision-induced dissociation citrate 17 clastogenicity 171, 205, 206 cognitive function 99 collision-induced dissociation (CID) 143 colorectal cancer 177 colostrum 136 Comet assays 147, 200, 202, 208 conalbumin 19 corticosterone 100 cows’ milk 58, 192 Cr(II) 205 Cr(III) x–xi Cr(IV) 135, 154 Cr(V) 135, 154 Cr(VI) ix–x, 136 Cr3 114, 147–9, 151 as chromium supplement 176–9 toxicology 177, 208 CRC454, see Chromium454 Cr(D-phenylalanine)3 112, 156, 174–5 CrNano 173 Cr–peptide complexes 149 Cr(phenylalanine)3 152 CrSP see chromium small peptide complexes cytokines 154–5 depression 99 dermal cells 200 dermatitis 204 dexamethasone 98 diabetes adult-onset see diabetes type (adult-onset diabetes) gestational 23, 85, 98 Trim: 229mm X 152mm INDEX steroid-induced 98 streptozotocin-induced 37, 100, 147, 173 type 22, 82, 113 type see diabetes type (adult-onset diabetes) diabetes type 22, 82, 113 diabetes type (adult-onset diabetes) 21–2, 215 and chromium picolinate 3–4 characteristics 81–2 human studies 85–98, 114–15 rat studies 83–4, 102–14 Diachrome 169 dichromate ix, 178 dietary stresses 48 and urinary chromium losses 21, 140 diets AIN-93G 10 chromium content in 2, 85 chromium-deficient 8–11, 24, 42 chromium-restricted 23 high-cholesterol 46, 47 high-fat 9, 113 high-sucrose 9, 46, 47 low-chromium 8, 10, 44, 47, 48 seed rye 45 Torula yeast-based 31–2, 33, 34, 41, 43–7 2,5-dimethoxy-4-iodophenyl-2aminopropane 100 dimethylsulfoxide (DMSO) 199, 200 Dinakrome 174 Dinatec 174 DMSO see dimethylsulfoxide DMT1 13 DNA cleavage 205, 206, 208 DNA damage and chromium histidine 173 and chromium nicotinate 207 and chromium picolinate 200–7 see also DNA cleavage dog liver 133 dose effect 97 Drosophila 200–1, 208 see also fruit flies dysthymic disorder 99, 204 Edman degradation 134, 143 EDTA (ethylenediaminetetraacetate) 17 EFSA see European Food Safety Authority electron paramagnetic resonance (EPR) spectroscopy x–xi, 170, 173 August 17, 2012 11:43 JWST232-bind JBST232-Vincent Printer: Yet to Come INDEX electron spin resonance (ESR) spectroscopy x–xi, 19, 135 encephalopathy 11 EPR spectroscopy see electron paramagnetic resonance (EPR) spectroscopy ESADDI see Estimated Safe and Adequate Daily Dietary Intake ESR spectroscopy see electron spin resonance (ESR) spectroscopy essentiality definition of 24 of chromium 2–3, 7–25, 215 Estimated Safe and Adequate Daily Dietary Intake (ESADDI) 169 euglycemic hyperinsulinemic clamp 21, 139–40 European Food Safety Authority (EFSA) 4, 176 European Union 176, 191 exanthematous pustulosis 204 exercise 46, 59, 63–9, 72 and urinary chromium losses 23 farm livestock 189–92 fasting glucose 9, 96, 98, 111 and chromic acetate 46 and chromium histidine 113 and chromium nicotinate 111 and chromium picolinate 88, 89, 90, 92, 102, 110, 112 and chromium pidolate 89, 176 and CrCl3 86, 87, 89, 91 and Cr yeast 92, 97 fasting insulin 10, 48, 93, 110, 147 and chromium histidine 113 and chromium picolinate 70–1, 88, 89, 90, 98, 110, 112, 151 and Cr3 110 and CrCl3 9, 87, 91 and Cr-enhanced yeast 90 fat mass 66, 67, 68, 72, 101 FDA see Food and Drug Administration Federal Trade Commission (FTC) 1–2, 72, 215 FEEDAP see Panel on Additives and Products or Substances Used in Animal Feed ferroportin 13 ferroxidase 13 fertility 46 fibre 67 fish 190 Trim: 229mm X 152mm August 17, 2012 11:43 221 food chromium in cravings 70 see also food intake Food and Drug Administration (FDA) 3–4, 191 food intake 10, 47, 48, 111 and chromium nanoparticles 173 and chromium nicotinate 207 and chromium picolinate 2, 70, 71, 100, 102, 110, 202 and chromium histidine 113 and Cr3 110 fruit flies 206 see also Drosophila FTC see Federal Trade Commission FutureCeuticals 173 Gab-1 126, 127 GainersFuel 65 gender 15–16, 63–4, 66, 91 genotoxicity 147, 199 gestation 207 see also pregnancy gestational diabetes 23, 85, 98 Glu4 Asp2 Gly 143 glucose 86, 96, 102, 111, 146 and CDNC 110 and chromium picolinate 88, 89, 93, 98, 101, 102, 110, 112, 113 and chromium-spirula 90 and CRC454 173 and CrCl3 87, 113 and Cr(D-phenylalanine)3 112 and Cr yeast 89 and chromium nicotinate 88, 111 intolerance 11, 31–2, 98 metabolism 32, 38, 41–2, 96–8, 101, 136 see also fasting glucose glucose tolerance factor (GTF) 31–43 and Brewer’s yeast 31, 32, 33, 35–9, 42 and porcine kidney powder 32, 33, 40 attempts at identification 31–4 synthetic 42–3 terminology 33 glucose tolerance tests (GTT) and chromium picolinate 93, 110, 112, 113 and Cr(D-phenylalanine)3 112 and CrCl3 86, 89, 113 glucose transport 137, 147, 159 JWST232-bind JBST232-Vincent Printer: Yet to Come 222 glucose uptake 23, 34, 37, 127, 144 and chromium picolinate 149, 152, 157 and CrCl3 149, 156 and Cr(D-phenylalanine)3 152, 156 and Cr-histidine 151, 157 and Cr-peptide 149 and CrSP 174 GLUT4 149, 151, 152, 156, 157, 159, 174 glutathione 37, 203 glycated haemoglobin 93, 111, 147 and Brewer’s yeast 86 and CDNC 110 and chromium nicotinate 110 and chromium picolinate 59, 87–93, 96, 110, 111 and chromium pidolate 89, 176 and Cr3 110–11 and CrCl3 91 and Cr yeast 90–2 glycogen synthase 149, 156, 174 graphite furnace atomic absorption spectrometry Grb2 126 GTF see glucose tolerance factor HaCaT keratinocytes 200 HDL see high-density lipoprotein (HDL) cholesterol hepatitis 172 hepatocytes 38, 147–8, 156, 177, 202 hepcidin 13 hephaestin 13 high-cholesterol diet 46, 47 high-density lipoprotein (HDL) cholesterol 93, 98, 146, 147 and biomimetic for LMWCr 145 and Brewer’s yeast 86 and chromium histidine 173 and chromium nicotinate 88, 111 and chromium picolinate 87, 88, 89, 91, 93, 101, 110, 152 and chromium pidolate 89, 176 and Cr3 110 and CrCl3 86, 87, 89 and Cr(D-phenylalanine)3 112 and Cr yeast 89, 90–2 high-fat diet 9, 113 high-sucrose diet 9, 46, 47 high valent chromium species 204, 205, 208 Hill plots 143 HIV 101–2 Trim: 229mm X 152mm INDEX 1H NMR spectroscopy 74, 134 NMR spectroscopy 74, 170 horses 190 hydrogen peroxide 153–4, 208 5-hydrohymethyl uracil 203 8-hydroxydeoxyguanosine (8-OHdG) 201, 203 hydroxyl radicals 205 5-hydroxytryptophan 100, 204 hypo-A Chrom 99 hypoglycaemia 155, 204 2H ICP-MS see inductively coupled plasma mass spectrometry IGF-1 see insulin-like growth factor IL-6 see interleukin-6 inductively coupled plasma mass spectrometry (ICP-MS) insulin dose response 136–7 insulin levels 86, 96, 146, 147 and chromium nanoparticles 173–4 and chromium nicotinate 88, 101 and chromium picolinate 88–90, 93, 98, 101, 102, 110, 112, 113 and chromium pidolate 176 and CrCl3 87, 113 and Cr(D-phenylalanine)3 112 and Cr yeast 89 insulin-like growth factor (IGF-1) 174 insulin receptor (IR) 125–6, 137, 138, 140, 142, 156 chromium binding to 149–51 insulin receptor number 155 insulin receptor substrate (IRS-1) 126, 127, 151, 152, 153, 157, 207 insulin resistance 22, 98, 111, 125, 155 and chromium picolate 3, 89 and Cr3 177 and CrCl3 91 and Cr yeast 92 and diabetes 81–2 and nicotinic acid 171 and urinary chromium losses 82, 84 insulin sensitivity 10, 102, 125, 154, 159 and biomimetic for LMWCr 146 and chromium picolinate 4, 92 and Cr3 177, 178 insulin signaling pathway 125–7, 149–50 InterHealth Nutraceutical 171, 172, 195, 207 interleukin-6 (IL-6) 155 August 17, 2012 11:43 JWST232-bind JBST232-Vincent Printer: Yet to Come INDEX intestinal perfusate 13–14, 17 IR see insulin receptor iron absorption of 12–13 transport of 18 IRS-1 see insulin receptor substrate isonicotinic acid 55 Kemin Americas 177 Kemtrace 176–8, 208 kidney and chromium excretion 131 and LMWCr 132, 133 failure 204 function 111 increased catalase 203 kynurenine pathway 204 L5178Y cells 172, 200, 207 L6 cells 148, 155–6, 174 Labcatal Pharmaceutical 175 lactation 85, 191, 207 lactoferrin 19 Langmuir isotherms 143 LBM see lean body mass LD50 of chromium nicotinate 207 of Cr3 147, 177, 208 of LMWCr 140 LDL see low-density lipoprotein (LDL) cholesterol lean body mass (LBM) 59, 63, 64, 65, 67, 69 learning rates 99 leptin 102, 111, 114 life span 59 linoleic acid 70 lipid metabolism 98, 111, 125, 142, 148, 216 lipid peroxidation 154–5, 201, 203, 207 lipids 96, 111, 136, 177 liver and chromium excretion 131 and LMWCr 132, 133, 134 bovine 133–5, 137, 143 dysfunction 204 necrosis of 172 LMWCr see low-molecular-weight chromium-binding substance low-chromium diet 8, 10, 44, 47, 48 see also chromium-deficient diet; chromium-restricted diet Trim: 229mm X 152mm August 17, 2012 11:43 223 low-density liporotein (LDL) cholesterol and biomimetic for LMWCr 145, 146, 147 and chromium nicotinate 88 and chromium picolinate 58, 88, 89, 91, 93, 101, 110 and Cr3 110 and CrCl3 87 and Cr yeast 89, 90–2 low-molecular-weight chromium-binding substance (LMWCr) 40, 127, 129, 132–44 synthetic models of 144–9 LD50 for 140 lungs 132 lymphocytes 199–200, 202, 206, 208 magnetic susceptibility studies 19, 135, 173 MALDI-TOF mass spectrometry 134 malondialdehyde 203, 206 manganese 23, 41 MAPK 151, 152, 157 mass spectrometry (MS) 134, 143, 170 maze tests 100 MCT see monocarboxylate transporters metabolic syndrome 70, 92 metformin 89 methanol 200 mice 133 C2C12 cells 144, 151, 155–6 effects of LMWCr injection140 forced swimming tests 100 L5178Y cells 172, 200, 207 models of diabetes 111–12 testis cells 144 toxicology studies on 202, 203–4, 208 MicroPlex1000 176 mitochondria 34 damage to 199 monocarboxylate transporters (MCT) 17 mood disorders 99 motor changes 204 MS see mass spectrometry murine macrophages 199 mutagenicity 199, 200 National Academy of Sciences 2, 215, 169 National Center for Biotechnology Information (NCBI) 144 National Institutes of Health 2, 4, 81 National Research Council 4, 189 JWST232-bind JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm 224 NCBI see National Center for Biotechnology Information neonates 113 neuropathy 11 neutron activation analysis nicotinate (3-carboxypyridine) 36–7, 42–3, 170 nicotinic acid 36, 170, 171, 207 NMR spectroscopy x, 43, 74, 134, 143, 170, 176 Nutrition 21 3, 58, 169, 172 obesity 3, 57, 111, 215 oestrogen 155 8-OHdG see 8-hydroxydeoxyguanosines oxalate 14 oxidative damage 90, 154, 201, 205–6 oxidative stress 90, 154, 171 Panel on Additives and Products or Substances Used in Animal Feed (FEEDAP) 191 PCOS see polycystic ovary syndrome perceptual changes 204 phospholipids 86 phosphotyrosine phosphatase (PTP) 137, 138, 152 phosphotyrosine protein phosphatase 1B (PTP1B) 127, 149 phyate 14 PI3K (phosphatidylinositol 3-kinase) 126–7, 152, 153, 156, 157 picolinic acid 55, 57, 58, 73–4 absorption 56 and neurological effects 100, 204, 205 toxicity, 199, 201 N-picolinoylglycine 57 pidolate 175–6 pigs see swine polycystic ovary syndrome (PCOS) 102 porcine kidney 133 porcine kidney powder 32, 33, 40, 133 post-source decay (PSD) 143 poultry 178, 190, 191 see also chicken liver pregnancy and chromium nicotinate 207 and chromium picolinate 203 and chromium-restricted diet 23 and urinary chromium losses 23, 82, 85 see also gestational diabetes PSD see post-source decay PTP see phosphotyrosine phosphatase INDEX PTP1B see phosphotyrosine protein phosphatase 1B pyridinecarboxylic acids 55 QTc interval 90 rabbits 133, 134, 140, 190 rat basophilic leukaemia (RBL-2H3) cells 207 rats alloxan-treated 84, 113 chromium-deficient 39, 45 effects of injection of LMWCr 140 force swimming tests 100 Goto–Kakizaki 112 JCR:LA-cp 102, 151 L6 skeletal muscle cells 148, 155–6, 174 maze tests 100 models of type diabetes 83–4, 102–14 nutritional studies 9–11, 43–8 Sprague–Dawley 100, 101, 173, 203, 207, 208 streptozotocin-treated rats 37, 100, 113, 146, 147, 152–3, 173 toxicology studies 201–3, 207, 208 Wistar 147, 208 Zucker diabetic fatty (ZDF) 83–4, 102, 110, 147 Zucker lean 83–4, 111 Zucker obese 83–4, 102, 110–11, 146, 147, 203 RBL-2H3 cells see rat basophilic leukaemia (RBL-2H3) cells reactive oxygen species (ROS) x, 154, 200, 203, 205 redox potential 74–5, 205 renal failure 204 renal function 111 rhabdomyolysis 204 ROS see reactive oxygen species Saccharomyces cerevisiae 38, 173 Salmonella typhimurium 172 satiety 70 serotonin 100 Shc 126 sheep 175, 190 skeletal muscle cells 149 C2C12 144, 151, 155–6 L6 148, 155–6, 174 solubility 148 sperm count 46 spleen 131, 132 August 17, 2012 11:43 JWST232-bind JBST232-Vincent Printer: Yet to Come Trim: 229mm X 152mm INDEX sterility 201 steroid-induced diabetes 98 streptozotocin 113 see also streptozotocin-treated rats streptozotocin-treated rats 37, 100, 113, 146, 147, 152–3, 173 stress 189 in livestock 190, 192 see also dietary stresses sulfonylurea 89, 91 superoxide dismutase 203 swimming tests 99, 100 swine feed suplements 4, 176, 178, 190, 191 toxicology studies 203 tandem mass spectrometry 143 TBARS see thiobarbituric acid reactive substances T-cells 200 thiobarbituric acid reactive substances (TBARS) 90, 92, 176, 203 thrombocytopenia 204 Torula yeast-based diet 31–4, 41, 43–7 total parenteral nutrition (TPN) 11–12 toxic hepatitits 172 toxicology 195–209 Ames assays 198–9, 207 cell culture studies 199–200 chromium nicotinate 172, 207–8 chromium picolinate 73, 157, 195–207 Cr3/Kemtrace 177, 208 Drosophila studies 200–1, 208 in vitro versus in vivo studies 202, 204–7 mammalian studies 201–4, 207, 208 neurological effects 204 TPN see total parenteral nutrition transferrin 13, 18–20, 127, 129 trauma 23 trifluoroacetic acid (TFA) 143 triglycerides 86, 93, 98, 102 and biomimetic for LMWCr 145, 146, 147 and Brewer’s yeast 86 and chromium nicotinate 88, 111 and chromium picolate 70–1, 88, 89, 93, 98, 101, 102, 110, 113 August 17, 2012 11:43 225 and chromium-spirula 90 and Cr3 110–11 and CrCl3 87, 89, 113 and Cr(D-phenylalanine)3 112 and Cr yeast 89, 90–2 tryptophan 100, 204 tyrosine kinase 137–8, 149–50, 155 uncoupling protein-3 149, 156, 174 United States 176, 178, 191 United States Department of Agriculture (USDA) 58 University of Alabama 177 urinary chromium losses 21–3 and dietary stresses 21, 140 and exercise 23 and HIV 101 and insulin resistance 82, 84–5 and pregnancy 23, 82, 85 urine and chromium excretion 127–9 LMWCr from 132 USDA see United States Department of Agriculture vanadate 151, 152–3, 154, 157 vanadium 153, 154 very low-density lipoprotein (VLDL) 87 VLDL see very low-density lipoprotein weight loss 204 XANES see X-ray absorption near edge spectroscopy X-ray absorption near edge spectroscopy (XANES) 148–9 X-ray absorption spectroscopy 135 X-ray crystallography 74, 173, 178 yeast see Brewer’s yeast; chromiumenhanced yeast; chromium yeast; Torula yeast-based diet Yucca shidigera 174 zinc 23 ZinPro 176 ... 152mm THE BIOINORGANIC CHEMISTRY OF CHROMIUM The fate of chromium in the bloodstream is somewhat better elucidated In vivo administration of chromic ions to mammals by injection results in the. .. considered carefully because of the variable amount of chromium that comes from soil contamination [16] The low concentrations of chromium in food, the ease of contamination and the low adequate intake(AI)... BIOINORGANIC CHEMISTRY OF CHROMIUM For this discussion, the most notable features of these studies are the level of Cr administered In the cases where deficiencies were reported, the TPN solutions