期刊
CHEMICAL RESEARCH IN TOXICOLOGY
卷 21, 期 7, 页码 1396-1406出版社
AMER CHEMICAL SOC
DOI: 10.1021/tx8000362
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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 (Cl(2)CA). 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 Cl(2)CA will form persistent (weeks to months) adducts to proteins, in analogy with the glucuronide conjugates of structurally related drugs. The 3-PBA and Cl(2)CA beta-glucuronide metabolites of permethrin have been successfully chemically and enzymatically synthesized. Their identities have been assessed by means of H-1 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 [C-14]-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.
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