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ToxSci Advance Access published online on March 2, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi138
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received January 19, 2005
Accepted February 24, 2005

Biotransformation and Toxicokinetics

IDENTIFICATION OF RAPID DETOXIFICATION MECHANISM OF BREVETOXIN IN RATS

Faisal F. Y. Radwan 1, Zhihong Wang 2, and John S. Ramsdell 2*

1 Marine Biotoxins Program, Center for Coastal Environmental Health and Biomedical Research, NOAA/National Ocean Service, 219 Fort Johnson Road, Charleston, SC 29412; Faculty of Science at Sohag, South Valley University, Egypt
2 Marine Biotoxins Program, Center for Coastal Environmental Health and Biomedical Research, NOAA/National Ocean Service, 219 Fort Johnson Road, Charleston, SC 29412

* To whom correspondence should be addressed.
John S. Ramsdell, E-mail: john.ramsdell{at}noaa.gov


  Abstract

We examined detoxification of brevetoxin in rats through metabolic activities and key elimination routes by analyzing samples from individual rats exposed to two brevetoxin congeners (PbTx-2 and PbTx-3). Brevetoxins were detected by radioimmunoassay in methanolic extracts of blood within 1 h post intraperitoneal (i.p.) administration. The toxin assay response was about three times higher in PbTx-2-treated rats vs. the same dose (180 µg/kg) of PbTx-3. This difference persisted for up to 8 h post-exposure. When the blood samples were re-extracted with 20% methanol to enhance recovery of potential polar brevetoxin metabolites, 25-fold higher assay activity was present in the PbTx-2 treated rats. Analysis of urine from the same animals identified 7-fold more activity in the PbTx-2 treated rats that accumulated over the course of 24 h. Radioimmunoassay-guided high performance liquid chromatographic analysis of urine from PbTx-2 treated rats yielded three major peaks of activity. The first peak was attributed to the two cysteine adducts, cysteine-PbTx sulfoxide and cysteine-PbTx (MH+: m/z 1034 and 1018). The second peak was attributed to the oxidized form of PbTx-2 (MH+: m/z 911) and its reduction product PbTx-3. The third peak remains unidentified. Brevetoxin cysteine conjugate and its sulfoxide product contributed nearly three quarters of the brevetoxin immunoactivity. Our findings indicate the most commonly occurring PbTx-2 is rapidly transformed to a polar metabolite of a reduced biological activity that appears in blood and remains for up to 8 h, yet is cleared mostly to the urine within 24 h.

Keywords: brevetoxins; brevetoxin metabolism; Karenia brevis; harmful algal bloom.
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