title: Identification of a rapid detoxification mechanism for brevetoxin in rats.
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 (ip) administration. The toxin assay response was about three times higher in PbTx-2-treated rats versus the same dose (180 microg/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.
authors.affiliation: Marine Biotoxins Program, Center for Coastal Environmental Health and Biomedical Research, NOAA/National Ocean Service, 219 Fort Johnson Road, Charleston, South Carolina 29412, USA.
authors.forename: Faisal F Y
authors.initials: FF
authors.lastname: Radwan
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.forename: John S
authors.initials: JS
authors.lastname: Ramsdell
mesh_terms: D000818:Animals; D002240:Carbohydrate Sequence; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000652:urine; D008658:Inactivation, Metabolic; D007202:Indicators and Reagents; D007274:Injections, Intraperitoneal; D008297:Male; D008387:Marine Toxins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D035964:Oxocins / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D011863:Radioimmunoassay; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism; D000095702:Polyether Toxins
chemical_list: D003545:Cysteine; D007202:Indicators and Reagents; D008387:Marine Toxins; D035964:Oxocins; D011955:Receptors, Drug; C051732:Ptychodiscus brevis T2 toxin; C041017:brevetoxin T17; D000095702:Polyether Toxins; C053342:brevetoxin