ToxSci Advance Access originally published online on March 2, 2005
Toxicological Sciences 2005 85(2):839-846; doi:10.1093/toxsci/kfi138
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Identification of a Rapid Detoxification Mechanism for Brevetoxin in Rats
* Marine Biotoxins Program, Center for Coastal Environmental Health and Biomedical Research, NOAA/National Ocean Service, 219 Fort Johnson Road, Charleston, South Carolina 29412, and Faculty of Science at Sohag, South Valley University, Egypt
Received January 19, 2005; accepted February 24, 2005
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 (ip) administration. The toxin assay response was about three times higher in PbTx-2-treated rats versus the same dose (180 µg/kg) of PbTx-3. This difference persisted for up to 8 h postexposure. When the blood samples were reextracted 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.
Key Words: brevetoxins; brevetoxin metabolism; Karenia brevis; harmful algal bloom.
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