Title
Protein adduct formation by glucuronide metabolites of permethrin
Author
Noort, D.
van Zuylen, A.
Fidder, A.
van Ommen, B.
Hulst, A.G.
TNO Defensie en Veiligheid
Publication year
2008
Abstract
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.
Subject
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
To reference this document use:
http://resolver.tudelft.nl/uuid:f91594a7-90b9-4924-ab3a-d19f44103188
DOI
https://doi.org/10.1021/tx8000362
TNO identifier
240902
ISSN
0893-228X
Source
Chemical Research in Toxicology, 21 (7), 1396-1406
Document type
article