Skip Navigation



ToxSci Advance Access published online on October 12, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj013
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
89/1/57    most recent
kfj013v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Radwan, F. F. Y.
Right arrow Articles by Ramsdell, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Radwan, F. F. Y.
Right arrow Articles by Ramsdell, J. S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
J. S. Morey, J. C. Ryan, M.-Y. Bottein Dechraoui, A. H. Rezvani, E. D. Levin, C. J. Gordon, J. S. Ramsdell, and F. M. Van Dolah
Liver Genomic Responses to Ciguatoxin: Evidence for Activation of Phase I and Phase II Detoxification Pathways following an Acute Hypothermic Response in Mice
Toxicol. Sci., June 1, 2008; 103(2): 298 - 310.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.