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New study reports evidence for carcinogenic chromium(VI) compounds in chromium(III)-treated living cells


Chromium supplements are often advertised for their antidiabetic activity as chromium(III) is reported to enhance the insulin sensitivity of cells. In particular, orthomolecular practitioners believe in the beneficial effects of providing the body with extra amounts of essential trace elements. Thus it has been proposed that the daily intake of a certain amount of chromium lowers the blood glucose level.

However, in higher oxidation states, chromium compounds can have detrimental effects causing oxidative stress and in its highest oxidation state hexavalent chromium is classified as cancerogen. For this reason there is growing concern about possible oxidation pathways during the metabolic transformation of the chromium(III)-containing drugs in the cell.

The new study:
With the aim at getting more insight into the metabolism of the chromium compounds after their intake at the cellular level, Peter A. Lay from the University of Sydney, Australia, and his colleagues employed X-ray fluorescence microscopy (XFM) elemental mapping and microfocus X-ray absorption near-edge structure (µ-XANES) analysis on single chromium(III)-treated adipocytes.

µXRF mapping of P and Cr in a cell together with XANES spectrum 
Making use of the Australian Synchrotron facility and of resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, XFM imaging provided a spatial resolution of 0.5 µm, while µ-XANES measurements where done in measurement spots of 1x1 µm.

By carrying out XFM analysis, Lay and his colleagues found that the chromium was confined in "hotspots", and the µ-XANES data revealed that these hotspots did not only contain chromium(III). The authors conclude: "This finding unambiguously confirmed the presence of high oxidation states of chromium." After having established the presence of higher oxidation states, the scientists also modelled the possible chromium compounds and identified chromium(V) and chromium(VI) compounds.

The question remained why the chromium was oxidized in the overall reducing environment of the cells. While photooxidation during irradiation was excluded, the authors present a possible and plausible explanation: During cell signaling, and especially insulin signaling, strong oxidants such as hydrogen peroxide are formed, which will trigger the formation of reactive chromium(V) and chromium(VI) intermediates. "This raises concern over the possible carcinogenicity of chromium(III) compounds and the risks of long-term chromium(III) nutritional supplementation," the authors say.

Although concerns have been raised for some time about the efficacy and safety of such supplements (see earlier EVISA News), many authorities and a large community of orthomolecular practitioners still recommend such treatments. Thus Lay and his colleagues urge for future studies: "In light of these findings, there is a need for epidemiological studies to ascertain whether chromium(III) supplements alter cancer risk".

Source: adapted from http://www.wiley.com/

The original studies

Lindsay E. Wu, Aviva Levina, Hugh H. Harris, Zhonghou Cai, Barry Lai, Stefan Vogt, David E. James, and Peter A. Lay, Carcinogenic Chromium(VI) Compounds Formed by Intracellular Oxidation of Chromium(III) Dietary Supplements by Adipocytes, Angew. Chem. Int. Ed., 55 (2016) 1742-1745. DOI:10.1002/anie.201509065

 Related Studies (newest first)

Zhijia Fang, Min Zhao, Hong Zhen, Lifeng Chen, Ping Shi, Zhiwei Huang, Genotoxicity of Tri- and Hexavalent Chromium Compounds In Vivo and Their Modes of Action on DNA Damage In Vitro. PLoS ONE 9/8 (2014) e103194. doi:10.1371/journal.pone.0103194

Graham N. George, Ingrid J. Pickering, M. Jake Pushie, Kurt Nienaber, Mark J. Hackett, Isabella Ascone, Britt Hedman, Keith O. Hodgson, Jade B. Aitken, Aviva Levina, Christopher Glover, Peter A. Lay, X-ray-induced photo-chemistry and X-ray absorption spectroscopy of biological samples, J. Synchrotron Rad. (2012). 19, 875–886. doi: 10.1107/S090904951203943X

Annie Nguyen, Irma Mulyani, Aviva Levina, Peter A. Lay, Reactivity of Chromium(III) Nutritional Supplements in Biological Media: An X-Ray Absorption Spectroscopic Study, Inorg. Chem., 47 (2008) 4299-4309. DOI: 10.1021/ic7024389

Aviva Levina, Peter A. Lay, Chemical Properties and Toxicity of Chromium(III) Nutritional Supplements, Chem. Res. Toxicol. 2008, 21, 563–571. doi: 10.1021/tx700385t

Aviva Levina, Hugh H. Harris, Peter A. Lay, X-ray Absorption and EPR Spectroscopic Studies of the Biotransformations of Chromium(VI) in Mammalian Cells. Is Chromodulin an Artifact of Isolation Methods?, J. Am. Chem. Soc., 129/5 (2007) 1065–1075. DOI: 10.1021/ja063792r

Maria A. Andersson, Kierstin V. Petersson Grawe, Oskar M. Karlsson, Lilianne A.G. Abramsson-Zetterberg, Björn E. Hellman, Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro, Food Chem. Toxicol., 45 (2007) 1097–1106. doi:10.1016/j.fct.2006.11.008

Aviva Levina, Irma Mulyani, Peter A. Lay, Redox chemistry and biological activities of chromium(III) complexes, in: John B. Vincent, The Nutritional Biochemistry of Chromium(III), Elsevier, Amsterdam, 2007, 225-256. DOI: 10.1016/B978-044453071-4/50012-6

Richard Ortega, Barbara Fayard, Murielle Salomé, Guillaume Devčs, Jean Susini, Chromium Oxidation State Imaging in Mammalian Cells Exposed in Vitro to Soluble or Particulate Chromate Compounds, Chem. Res. Toxicol., 18 (2005) 1512-1519. DOI: 10.1021/tx049735y

Hugh H. Harris, Aviva Levina, Carolyn T. Dillon, Irma Mulyani, Barry Lai, Zhonghou Cai, Peter A. Lay, Time-dependent uptake, distribution and biotransformation of chromium(VI) in individual and bulk human lung cells: application of synchrotron radiation techniques, J. Biol. Inorg. Chem.,  10 (2005) 105–118. DOI 10.1007/s00775-004-0617-1

 Irma Mulyani, Aviva Levina, A. Lay, Biomimetic Oxidation of Chromium(iii): Does the Antidiabetic Activity of Chromium(iii) Involve Carcinogenic Chromium(VI)?, Angew. Chem., 43/34 (2004) 4504-4507. DOI: 10.1002/anie.200460113

Aviva Levina, Lianbo Zhang, Peter A. Lay, Structure and Reactivity of a Chromium(V) Glutathione Complex, Inorg. Chem., 2003, 42/3 (2003) 767–784.
DOI: 10.1021/ic020621o

Related information

EFSA: Scientific Opinion on Dietary Reference Values for chromium
NIH: Dietary Supplement Fact Sheet: Chromium

 Related EVISA Resources

Link Database: Chromium as an essential nutrient
Link Database: ATSDR: Toxicological Profile for Chromium
Link Database: More about Cr(III)/Cr(VI)
 Link Database: Toxicity of hexavalent chromium (chromate)
Link Database: Legislation related to chromium
 Link Database: Methods for chromium speciation analysis 

Brief summary: ICP-MS: A versatile detection system for trace element and speciation analysis
Brief summary: LC-ICP-MS - The most often used hyphenated system for speciation analysis 

 Related EVISA News (newest first)

January 8, 2016: New study reports evidence for carcinogenic chromium(VI) compounds in chromium(III)-treated living cells
October 19, 2014: EFSA: No evidence for essentiality of chromium
August 18, 2014: New research indicates that chromium (III) is even more genotoxic than chromium (VI)
November 24, 2010: Deemed Essential to Health for Decades, Chromium Has No Nutritional Effect, UA Researchers Show
May 23, 2007: Trivalent Chromium supplemention no help in controlling diabetes
April 24, 2007: Nutrigenomics: The role of chromium for fat metabolism revisited
September 15, 2005: FDA Approves Chromium Claim
March 20, 2005: United Kingdom's Food Standards Agency granted derogation to Chromium(III) compounds as a food supplement
November 23, 2004: Chromium (III) - not only therapeutic?

last time modified: September March 9, 2024


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