Semisynthesis of Radiolabeled Amino Acid and Lipid Brevetoxin Metabolites and Their Blood Elimination Kinetics in C57BL/6 Mice
| Autor: | Tod A. Leighfield, Christopher O. Miles, John S. Ramsdell, Noah Muha |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
0106 biological sciences Stereochemistry Tritium Toxicology complex mixtures 01 natural sciences Aldehyde Lethal Dose 50 Mice 03 medical and health sciences Brevetoxin Side chain Animals Cysteine 030304 developmental biology chemistry.chemical_classification 0303 health sciences Molecular Structure biology Chemistry 010604 marine biology & hydrobiology Oxocins Fatty acid General Medicine biology.organism_classification Semisynthesis Toxicokinetics Amino acid Mice Inbred C57BL Karenia Kinetics Biochemistry Marine Toxins |
| Zdroj: | Chemical Research in Toxicology. 26:868-877 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx4000057 |
| Popis: | Brevetoxin B (BTX-B), produced by dinoflagellates of the species Karenia, is a highly reactive molecule, due in part to an α,β-unsaturated aldehyde group at the terminal side chain, leading to the production of metabolites in shellfish by reduction, oxidation, and conjugation. We have investigated in mice the blood elimination of three common bioactive brevetoxin metabolites found in shellfish, which have been semisynthesized from BTX-B in radioactive forms. BTX-B was reduced at C42 to yield [(3)H] dihydro-BTX-B. [(3)H] S-desoxy-BTX-B2 (cysteine brevetoxin B) was semisynthesized from BTX-B by the conjugation of cysteine at the C50 olefinic group then [(3)H] radiolabeled by C42 aldehyde reduction. [(14)C] N-Palmitoyl-S-desoxy-BTX-B2 was prepared using S-desoxy-BTX-B2 as the starting material with addition of the [(14)C] radiolabeled fatty acid via cysteine-amide linkage. The elimination of intravenously administered [(3)H] S-desoxy-BTX-B2, [(14)C] N-palmitoyl-S-desoxy-BTX-B2, or [(3)H] dihydro-BTX-B was measured in blood collected from C57BL/6 mice over a 48 h period. Each brevetoxin metabolite tested exhibited biexponential elimination kinetics and fit a two-compartment model of elimination that was applied to generate toxicokinetic parameters. The rate of transfer between the central compartment (i.e., blood) and the peripheral compartment (e.g., tissue) for each brevetoxin differed substantially, with dihydro-BTX-B exchanging rapidly with the peripheral compartment, S-desoxy-BTX-B2 eliminating rapidly from the central compartment, and N-palmitoyl-S-desoxy-BTX-B2 eliminating slowly from the central compartment. Toxicokinetic parameters were analyzed in the context of the unique structure of each brevetoxin metabolite resulting from a reduction, amino acid conjugation, or fatty acid addition to BTX-B. |
| Databáze: | OpenAIRE |
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