Simultaneous measurement of 3-chlorotyrosine and 3,5-dichlorotyrosine in whole blood, serum and plasma by isotope dilution HPLC-MS-MS
Open accessAbstract
Chlorine is a public health concern and potential threat due to its high reactivity, ease and scale of production, widespread industrial use, bulk transportation, massive stockpiles and history as a chemical weapon. This work describes a new, sensitive and rapid stable isotope dilution method for the retrospective detection and quantitation of two chlorine adducts. The biomarkers 3-chlorotyrosine (Cl-Tyr) and 3,5-dichlorotyrosine (Cl2-Tyr) were isolated from the pronase digest of chlorine exposed whole blood, serum or plasma by solid-phase extraction (SPE), separated by reversed-phase HPLC and detected by tandem mass spectrometry (MS-MS). The calibration range is 2.50-1,000 ng/mL (R2 ≥ 0.998) with a lowest reportable limit (LRL) of 2.50 ng/mL for both analytes, an accuracy of ≥93% and an LOD of 0.443 ng/mL for Cl-Tyr and 0.396 ng/mL for Cl2-Tyr. Inter- and intra-day precision of quality control samples had coefficients of variation of ≤10% and ≤7.0%, respectively. Blood and serum samples from 200 healthy individuals and 175 individuals with chronic inflammatory disease were analyzed using this method to assess background levels of chlorinated tyrosine adducts. Results from patients with no known inflammatory disease history (healthy) showed baseline levels of <LRL-4.26 ng/mL Cl-Tyr and <LRL Cl2-Tyr. Patients with inflammatory disease had baseline levels of <LRL-15.4 ng/mL Cl-Tyr and
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Other identifiable chlorine adducts include 3-chlorotyrosine and 3,5-dichlorotyrosine, which are known to form after chlorine exposure and have been proposed as biomarkers of chlorine exposure.
“Other identifiable chlorine adducts include 3-chlorotyrosine and 3,5-dichlorotyrosine that are known to form after chlorine exposure and have been proposed as biomarkers of chlorine exposure (Crow et al., 2016).”
From Effects of exposure to water disinfection by-products in a swimming pool: A metabolome-wide association study (2018) · cites this paper as Crow et al., 2016
The relative retention times of the compounds support such identifications.
“The relative retention times of the compounds support such identifications (Crow et al., 2016) (see Fig. S6 for details).”
From Effects of exposure to water disinfection by-products in a swimming pool: A metabolome-wide association study (2018) · cites this paper as Crow et al., 2016
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Cites
Hazen, S. L., & Heinecke, J. W. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119379 · Cited by 842 · see citing works
Quality assurance of chemical measurements
Taylor, J. K., & Tranter, R. L. (1989) · Analytica Chimica Acta · doi:10.1016/s0003-2670(00)80373-6 · Cited by 690 · see citing works
Plasma Concentrations of Myeloperoxidase Predict Mortality After Myocardial Infarction
Mocatta, T. J., Pilbrow, A. P., Cameron, V. A., Senthilmohan, R., Frampton, C. M., Richards, M., & Winterbourn, C. C. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.02.040 · Cited by 344 · see citing works
Chlorination of Tyrosyl Residues in Peptides by Myeloperoxidase and Human Neutrophils
Domigan, N. M., Charlton, T. S., Duncan, M. W., Winterbourn, C. C., & Kettle, A. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.28.16542 · Cited by 329 · see citing works
Chlorine Gas Inhalation: Human Clinical Evidence of Toxicity and Experience in Animal Models
White, C. W., & Martin, J. G. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.201001-008sm · Cited by 328 · see citing works
Human neutrophils employ chlorine gas as an oxidant during phagocytosis.
Hazen, S. L., Hsu, F., Mueller, D. M., Crowley, J., & Heinecke, J. W. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118914 · Cited by 258 · see citing works
Tabassi, L. W. (2007) · Cambridge University Press eBooks · doi:10.1017/cbo9780511494345.013 · Cited by 249 · see citing works
Chlorination studies of free and combined amino acids
Hureïki, L., Croué, J.-P., & Legube, B. (1994) · Water Research · doi:10.1016/0043-1354(94)90070-1 · Cited by 223 · see citing works
Winder, C. (2001) · Environmental Research · doi:10.1006/enrs.2000.4110 · Cited by 205 · see citing works
Neutrophils convert tyrosyl residues in albumin to chlorotyrosine
Kettle, A. J. (1996) · FEBS Letters · doi:10.1016/0014-5793(95)01494-2 · Cited by 188 · see citing works
Acute health effects after exposure to chlorine gas released after a train derailment
Sickle, D. V., Wenck, M. A., Belflower, A., Drociuk, D., Ferdinands, J. M., Holguín, F., Svendsen, E. R., Bretous, L., Jankelevich, S., Gibson, J. J., et al. (2008) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2007.12.006 · Cited by 171 · see citing works
Myeloperoxidase and Protein Oxidation in the Airways of Young Children with Cystic Fibrosis
Kettle, A. J., Chan, T., Osberg, I. M., Senthilmohan, R., Chapman, A., Mocatta, T. J., & Wagener, J. S. (2004) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200311-1516oc · Cited by 148 · see citing works
Evans, R. B. (2005) · Lung · doi:10.1007/s00408-004-2530-3 · Cited by 141 · see citing works
Mass Spectrometric Quantification of 3-Chlorotyrosine in Human Tissues with Attomole Sensitivity
Hazen, S. L., Crowley, J. R., Mueller, D. M., & Heinecke, J. W. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(97)00084-1 · Cited by 134 · see citing works
Gaut, J. P., Byun, J., Tran, H. D., & Heinecke, J. W. (2002) · Analytical Biochemistry · doi:10.1006/abio.2001.5469 · Cited by 133 · see citing works
Myeloperoxidase-catalyzed 3-chlorotyrosine formation in dialysis patients
Himmelfarb, J., McMenamin, M. E., Loseto, G., & Heinecke, J. W. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00697-9 · Cited by 115 · see citing works
Fu, S., Wang, H., Davies, M. J., & Dean, R. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.10851 · Cited by 102 · see citing works
Wenck, M. A., Sickle, D. V., Drociuk, D., Belflower, A., Youngblood, C., Whisnant, M. D., Taylor, R., Rudnick, V., & Gibson, J. J. (2007) · Public Health Reports · doi:10.1177/003335490712200610 · Cited by 68 · see citing works
Chapman, A., Senthilmohan, R., Winterbourn, C. C., & Kettle, A. J. (2000) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2000.1744 · Cited by 65 · see citing works
Chlorine gas: an evolving hazardous material threat and unconventional weapon.
Jones, R. K., Wills, B., & Kang, C. (2010) · PubMed · Cited by 65 · see citing works
Crow, B. S., Pantazides, B. G., Quiñones-González, J., Garton, J. W., Carter, M. D., Perez, J. W., Watson, C. M., Tomcik, D. J., Crenshaw, M. D., Brewer, B. N., et al. (2014) · Analytical Chemistry · doi:10.1021/ac502886c · Cited by 62 · see citing works
Self-citationHUSSAIN, A. A., Trudell, P., & Repta, A. J. (1970) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600590824 · Cited by 54 · see citing works
Sochaski, M. A., Jarabek, A. M., Murphy, J., & Andersen, M. E. (2008) · Journal of Analytical Toxicology · doi:10.1093/jat/32.1.99 · Cited by 27 · see citing works
Šakić, D., Šonjić, P., Tandarić, T., & Vrček, V. (2014) · The Journal of Physical Chemistry A · doi:10.1021/jp5012846 · Cited by 22 · see citing works
When Chemicals Became Weapons Of War
EVERTS, S. (2015) · Chemical & Engineering News · doi:10.1021/cen-09308-cover1 · Cited by 7 · see citing works
Gussow, L. (2007) · Emergency Medicine News · doi:10.1097/01.eem.0000302950.52044.6b · Cited by 4 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [5]Smart JK 1997 History of Chemical and Biological Warefare: An American Perspective Zajtchuk R Bellamy RF Sidell FR Takafuji ET Franz DR Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare, Chapter 2 Borden Institute Washington, DC 13 15
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Sultana, S., Christeson, S. E., Basiouny, M. A., Rioux, J. S., Veress, L. A., & Logue, B. A. (2023) · Journal of Chromatography B · doi:10.1016/j.jchromb.2024.124042 · Cited by 4 · see citing works
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- Authors
- Crow, B. S., Quiñones-González, J., Pantazides, B. G., Perez, J. W., Winkeljohn, W. R., Garton, J. W., Thomas, J. D., Blake, T. A., & Johnson, R. C.
- Affiliations
- Centers for Disease Control and Prevention (US)
- Battelle (US)
- Corresponding author
- Crow, Brian S.
- Venue
- Journal of Analytical Toxicology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-13
- Volume
- 40
- Issue
- 4
- Pages
- 264-271
- ISSN
- 0146-4760 (ISSN-L)
- 1945-2403
- PMC
- PMC5693347
- OpenAlex
- W2308993340
- Cited by
- 38
- References
- 26
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 5 · 2018: 1 · 2017: 1 · 2016: 3
- FWCI
- 2.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Analytical Toxicology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Centers for Disease Control and Prevention
- Office of Public Health Preparedness and Response
- Oak Ridge Institute for Science and Education
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Pesticide Residue Analysis and Safety
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical chemistry methods development
- Keywords
- 3-chlorotyrosine, chlorine exposure, biomarkers, stable isotope dilution, whole blood, serum, plasma, solid-phase extraction, chronic inflammatory diseases
- MeSH terms
- Calibration, Chromatography, High Pressure Liquid, Humans, Indicators and Reagents, Inflammation, Plasma, Quality Control, Radioisotope Dilution Technique, Retrospective Studies, Tyrosine, Reproducibility of Results, Biomarkers, Solid Phase Extraction, Tandem Mass Spectrometry, Limit of Detection
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