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ToxSci Advance Access published online on October 12, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj013
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Published by Oxford University Press 2005.
Received August 22, 2005
Accepted September 30, 2005

Biotransformation and Toxicokinetics

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

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

1 Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA-National Ocean Service, Charleston, South Carolina 29412, USA; Faculty of Sciences at Sohag, South Valley University, Sohag 82524, Egypt
2 Marine Biotoxins Program, Center for Coastal Environmental Health and Biomolecular Research, NOAA-National Ocean Service, Charleston, South Carolina 29412, USA

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


  Abstract

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 including 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. A further identification of the metabolites produced by CYP1A2 and CYP3A1 was preformed using high performance liquid chromatography and mass spectrometry (LC/MS (/MS). Each of 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). A subsequent incubation of PbTx-2 with rat hepatocytes has produced four additional phase 1 metabolites of MH+: m/z 913, 915, 917, and 931 indicating an CYP-catalyzed epoxidation of H-ring (C27,C28-double bond) and a later epoxide reduction. A conjugation metabolism was identified by the production of a glutathione-brevetoxin conjugate (MH+: m/z 1222) and cysteine-brevetoxin conjugate (MH+: m/z 1018). Structures of the new metabolites were postulated and a likely CYP-catalyzed metabolism pathway of PbTx-2 metabolism was discussed.

Keywords: Karenia brevis; Red tide bloom; Brevetoxin; Metabolism; In vitro; Cytochrome P450; CYP; Conjugation.
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