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Semisynthesis of Radiolabeled Amino Acid and Lipid Brevetoxin Metabolites and Their Blood Elimination Kinetics in C57BL/6 Mice

Author(s): Leighfield, T.A.; N. Muha; C.O. Miles; J.S. Ramsdell

NCCOS Center: CCEHBR (http://coastalscience.noaa.gov/about/centers/ccehbr)

Publication Type: Journal Article

Journal Title: Chemical Research in Toxicology

Date of Publication: 2013

Reference Information: 26(6): 868-877

Abstract: Brevetoxin B (BTX-B), produced by dinoflagellates of the species Karenia, is a highly reactive molecule, due in part to an a,ß-unsaturated aldehyde group at the terminal side chain, leading to the production of metabolites 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 semi-synthesized from BTX-B in radioactive forms. BTX-B was reduced at C42 to yield [3H] dihydro-BTX-B. [3H] S-desoxy-BTX-B2 (cysteine brevetoxin B) was semi-synthesized from BTX-B by conjugation of cysteine at the C50 olefinic group, then [3H] radiolabeled by C42 aldehyde reduction. [14C] N-palmitoyl-S-desoxy-BTX-B2 was prepared using S-desoxy-BTX-B2 as the starting material with addition of the [14C] radiolabeled fatty acid via the cysteine-amide linkage. The elimination of intravenously administered [3H] S-desoxy-BTX-B2, [14C] N-palmitoyl-S-desoxy-BTX-B2, or [3H] dihydro-BTX-B was measured in blood collected from C57BL/6 mice over a 48 hour 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, and 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.

Availability: Tod.Leighfield@noaa.gov