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Review
. 2013 May 10;307:46-54.
doi: 10.1016/j.tox.2012.12.007. Epub 2012 Dec 20.

Protein Adducts as Biomarkers of Exposure to Organophosphorus Compounds

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Free PMC article
Review

Protein Adducts as Biomarkers of Exposure to Organophosphorus Compounds

Judit Marsillach et al. Toxicology. .
Free PMC article

Abstract

Exposure to organophosphorus (OP) compounds can lead to serious neurological damage or death. Following bioactivation by the liver cytochromes P450, the OP metabolites produced are potent inhibitors of serine active-site enzymes including esterases, proteases and lipases. OPs may form adducts on other cellular proteins. Blood cholinesterases (ChEs) have long served as biomarkers of OP exposure in humans. However, the enzymatic assays used for biomonitoring OP exposures have several drawbacks. A more useful approach will focus on multiple biomarkers and avoid problems with the enzymatic activity assays. OP inhibitory effects result from a covalent bond with the active-site serine of the target enzymes. The serine OP adducts become irreversible following a process referred to as aging where one alkyl group dissociates over variable lengths of time depending on the OP adduct. The OP-adducted enzyme then remains in circulation until it is degraded, allowing for a longer window of detection compared with direct analysis of OPs or their metabolites. Mass spectrometry (MS) provides a very sensitive method for identification of post-translational protein modifications. MS analyses of the percentage adduction of the active-site serine of biomarker proteins such as ChEs will eliminate the need for basal activity levels of the individual and will provide for a more accurate determination of OP exposure. MS analysis of biomarker proteins also provides information about the OP that has caused inhibition. Other useful biomarker proteins include other serine hydrolases, albumin, tubulin and transferrin.

Conflict of interest statement

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Bioactivation, adduct formation and aging on BChE of the organophosphates chlorpyrifos, diazinon, azinphos methyl and tri-ortho-cresyl phosphate.
Figure 2
Figure 2
Mass spectra showing the identification of BChE adducted active-site chymotryptic peptide by in vitro incubation with the active metabolite from tricresyl phosphate, cresyl saligenin phosphate (adapted from Marsillach et al. 2011). The asterisk (*) indicates an added mass of + 80 Da that corresponds to a phosphate group covalently bound to the serine 198 of the BChE active-site.

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