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ToxSci Advance Access originally published online on October 12, 2005
Toxicological Sciences 2006 89(1):57-65; doi:10.1093/toxsci/kfj013
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Published by Oxford University Press 2005.

Characterization of In Vitro Oxidative and Conjugative Metabolic Pathways for Brevetoxin (PbTx-2)

Faisal F. Y. Radwan*,{dagger} and John S. Ramsdell*,1

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

Received August 22, 2005; accepted September 30, 2005

Brevetoxins are potent marine toxins produced by the dinoflagellate Karenia brevis, the causative organism of Florida red tides. An in vitro metabolism of PbTx-2 was performed using purified cDNA-expressed rat liver cytochrome P-450 (CYP) enzymes and freshly isolated rat hepatocytes. The metabolic activities of six CYP enzymes, CYP1A2, CYP2A2, CYP2C11, CYP2D1, CYP2E1, and CYP3A1, were examined by incubation with PbTx-2 for up to 4 h in the presence of a NADPH-generating system. Further identification of the metabolites produced by CYP1A2 and CYP3A1 was preformed using high performance liquid chromatography-mass spectrometry (LC/MS). Both CYP1A2 and CYP3A1 metabolized PbTx-2 to PbTx-3 (MH+: m/z 897), PbTx-9 (MH+: m/z 899), and a newly recorded diol brevetoxin-2 metabolite (MH+: m/z 929). CYP3A1 also produced a considerably higher amount of BTX-B5 (MH+: m/z 911). Subsequent incubation of PbTx-2 with rat hepatocytes produced additional phase 1 metabolites of MH+: m/z 911, 913, 915, 917, and 931, indicating a CYP-catalyzed epoxidation at H-ring (C27,C28-double bond) and a subsequent A-ring hydrolysis of PbTx-2 metabolic products. A conjugation metabolism was identified by the production of a glutathione-brevetoxin conjugate (MH+: m/z 1222) and a cysteine-brevetoxin conjugate (MH+: m/z 1018). Structures of the new metabolites are postulated, and a likely CYP-catalyzed metabolism pathway of PbTx-2 metabolism are discussed.

Key Words: Karenia brevis; red tide bloom; brevetoxin metabolism; in vitro; cytochrome P450; CYP; conjugation.


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