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Protein adduct formation by glucuronide metabolites of permethrin

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Author: Noort, D. · Zuylen, A. van · Fidder, A. · Ommen, B. van · Hulst, A.G.
Institution: TNO Defensie en Veiligheid
Source:Chemical Research in Toxicology, 7, 21, 1396-1406
Identifier: 240902
doi: doi:10.1021/tx8000362
Keywords: Nutrition · 3 (2,2 dichlorovinyl) 2,2 dimethylcyclopropane 1 carboxylic acid · 3 phenoxybenzoic acid · Albumin · Amino acid · Benzoic acid derivative · Carboxylic acid derivative · Glucuronide · Lysine derivative · Peptide · Permethrin · Pronase · Article · Biological monitoring · Chemical structure · Complex formation · Covalent bond · Crug conjugation · Enzyme synthesis · Liquid chromatography · Metabolite · Protein adduct · Protein binding · Proton nuclear magnetic resonance · Radioactivity · Synthesis · Tandem mass spectrometry · Chromatography, High Pressure Liquid · Environmental Monitoring · Glucuronides · Humans · Insecticides · Lysine · Magnetic Resonance Spectroscopy · Microsomes, Liver · Permethrin · Pesticide Residues · Protein Binding · Serum Albumin · Spectrometry, Mass, Electrospray Ionization · Tandem Mass Spectrometry · Chemicals · 3 phenoxybenzoic acid, 3739-38-6 · Amino acid, 65072-01-7 · Permethrin, 51877-74-8, 52645-53-1 · Pronase, 9036-06-0 · Glucuronides · Insecticides · Lysine, 56-87-1 · Permethrin, 52645-53-1 · Pesticide residues · Serum albumin


Biomonitoring of exposure to the insecticide permethrin is usually performed by analysis of its urinary metabolites 3-phenoxybenzoic acid (3-PBA) or cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (Cl2CA). We are engaged in the development of a methodology to assess the cumulative internal dose of exposure to permethrin, which is based on the assumption that (reactive) glucuronide conjugates of the major permethrin metabolites 3-PBA and Cl2CA will form persistent (weeks to months) adducts to proteins, in analogy with the glucuronide conjugates of structurally related drugs. The 3-PBA and Cl2CA β-glucuronide metabolites of permethrin have been successfully chemically and enzymatically synthesized. Their identities have been assessed by means of 1H NMR spectroscopy and liquid chromatography-tandem mass spectrometry. The reactivity of these metabolites with various amino acids, peptides, and albumin in human plasma has been studied. Several distinct adducts could be identified by liquid chromatography-tandem mass spectrometry. After pronase digestion of albumin isolated from exposed human plasma, various lysine derivatives resulted with favorable mass spectrometric and chromatographic properties. Covalent binding was quantified by using [14C]-3-PBA glucuronide; >1.5% of total radioactivity was bound to proteins. It is envisaged that the obtained results can form a firm basis for the development of a protein adduct-based methodology for biomonitoring exposure to permethrin. In view of the widespread use of permethrin, the toxicological relevance of protein binding by its metabolites will be addressed in more detail in future work. © 2008 American Chemical Society.