Structural Characterization of Toxicologically Relevant Cd2+-L-Cysteine Complexes

Astha Gautam; Amanda Gomez; Emérita Mendoza Rengifo; Graham N George; Ingrid J Pickering; Jürgen Gailer

doi:10.3390/toxics11040294

Structural Characterization of Toxicologically Relevant Cd²⁺-L-Cysteine Complexes

Toxics. 2023 Mar 23;11(4):294. doi: 10.3390/toxics11040294.

Authors

Astha Gautam¹, Amanda Gomez¹, Emérita Mendoza Rengifo², Graham N George², Ingrid J Pickering², Jürgen Gailer¹

Affiliations

¹ Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada.
² Molecular and Environmental Science Research Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada.

Abstract

The exposure of humans to Cd exerts adverse human health effects at low chronic exposure doses, but the underlying biomolecular mechanisms are incompletely understood. To gain insight into the toxicologically relevant chemistry of Cd²⁺ in the bloodstream, we employed an anion-exchange HPLC coupled to a flame atomic absorption spectrometer (FAAS) using a mobile phase of 100 mM NaCl with 5 mM Tris-buffer (pH 7.4) to resemble protein-free blood plasma. The injection of Cd²⁺ onto this HPLC-FAAS system was associated with the elution of a Cd peak that corresponded to [CdCl₃]^-/[CdCl₄]^2- complexes. The addition of 0.1-10 mM L-cysteine (Cys) to the mobile phase significantly affected the retention behavior of Cd²⁺, which was rationalized by the on-column formation of mixed CdCys_xCl_y complexes. From a toxicological point of view, the results obtained with 0.1 and 0.2 mM Cys were the most relevant because they resembled plasma concentrations. The corresponding Cd-containing (~30 μM) fractions were analyzed by X-ray absorption spectroscopy and revealed an increased sulfur coordination to Cd²⁺ when the Cys concentration was increased from 0.1 to 0.2 mM. The putative formation of these toxicologically relevant Cd species in blood plasma was implicated in the Cd uptake into target organs and underscores the notion that a better understanding of the metabolism of Cd in the bloodstream is critical to causally link human exposure with organ-based toxicological effects.

Keywords: L-cysteine; bloodstream; cadmium; chloride; complex formation; toxicological chemistry.

Grants and funding

A. Gautam was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grant to J.G.). Research at the University of Saskatchewan was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC, Discovery Grants to G.N.G., I.J.P.), a New Frontiers in Research Fund Exploration Grant (G.N.G. and others), the University of Saskatchewan, and by Canada Research Chairs (G.N.G., I.J.P.). LIV is a Fellow in the NSERC CREATE to INSPIRE (I.J.P. and others). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, was supported by the U.S. Department of Energy (DOE), Office of Science, and Office of Basic Energy Sciences under contract number DE-AC02–76SF00515, respectively. The SSRL Structural Molecular Biology Program was supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393 and P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.