Document Detail

The algal hepatoxoxin okadaic acid is a substrate for human cytochromes CYP3A4 and CYP3A5.
MedLine Citation:
PMID:  19699225     Owner:  NLM     Status:  MEDLINE    
The hepatotoxin okadaic acid (OA) was incubated with nine human recombinant cytochrome P450s (1A1, 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 3A5). Both CYP3A4 and CYP3A5 converted OA to a mixture of the same four metabolites, but incubation with CYP3A4 resulted in higher levels of conversion. Michaelis-Menten parameters, K(m) (73.4 microM) and V(max) (7.23 nmol of metabolitesnmol(-1)min(-1)) for CYP3A4 were calculated by analyzing double-reciprocal plots. LC-MS(n) analysis and chemical interconversion indicate that metabolites 2 and 3 are the 11S-hydroxy and 11R-hydroxy okadaic acid respectively, while metabolite 4 is 11-oxo okadaic acid. LC-MS(n) analysis of metabolite 1 shows a molecular ion which corresponds to an addition of 16 amu to OA, also suggesting hydroxylation, but the specific site has not been identified. The same four metabolites were produced upon incubation of okadaic acid with pooled human liver microsomes. This transformation could be completely inhibited with ketokonazole, and inhibitor of the CYP3A family of enzymes. The metabolites were determined to be only slightly less potent inhibitors of serine threonine protein phosphatase 2A (PP2A) when compared to OA. As PP2A is the principle molecular target for OA, these oxidative transformations may not effectively detoxify OA.
Fujiang Guo; Tianying An; Kathleen S Rein
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2009-08-20
Journal Detail:
Title:  Toxicon : official journal of the International Society on Toxinology     Volume:  55     ISSN:  1879-3150     ISO Abbreviation:  Toxicon     Publication Date:    2010 Feb-Mar
Date Detail:
Created Date:  2010-01-29     Completed Date:  2010-04-08     Revised Date:  2014-09-22    
Medline Journal Info:
Nlm Unique ID:  1307333     Medline TA:  Toxicon     Country:  England    
Other Details:
Languages:  eng     Pagination:  325-32     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier Ltd. All rights reserved.
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MeSH Terms
Chromatography, High Pressure Liquid
Chromatography, Ion Exchange
Cytochrome P-450 CYP3A / antagonists & inhibitors,  metabolism*
Drug-Induced Liver Injury / enzymology*
Enzyme Inhibitors / metabolism*,  pharmacology
Liver / enzymology
Mass Spectrometry
Microsomes, Liver / enzymology
Okadaic Acid / metabolism*,  pharmacology
Protein Phosphatase 2 / antagonists & inhibitors
Recombinant Proteins / metabolism
Spectrometry, Mass, Electrospray Ionization
Xenobiotics / metabolism
Grant Support
P50 ES012736/ES/NIEHS NIH HHS; P50 ES012736-02/ES/NIEHS NIH HHS; P50 ES012736-02S1/ES/NIEHS NIH HHS; P50 ES012736-03/ES/NIEHS NIH HHS; P50 ES012736-03S1/ES/NIEHS NIH HHS; P50 ES012736-04/ES/NIEHS NIH HHS; P50 ES012736-05/ES/NIEHS NIH HHS; P50 ES012736-05S1/ES/NIEHS NIH HHS; P50 ES12736-01/ES/NIEHS NIH HHS; S11 ES011181/ES/NIEHS NIH HHS; S11 ES011181-06/ES/NIEHS NIH HHS; S11 ES011181-069002/ES/NIEHS NIH HHS; S11 ES011181-069003/ES/NIEHS NIH HHS; S11 ES011181-07/ES/NIEHS NIH HHS; S11 ES011181-079002/ES/NIEHS NIH HHS; S11 ES011181-079003/ES/NIEHS NIH HHS; S11 ES011181-08/ES/NIEHS NIH HHS; S11 ES011181-089002/ES/NIEHS NIH HHS; S11 ES011181-089003/ES/NIEHS NIH HHS; S11 ES011181-09/ES/NIEHS NIH HHS; S11 ES011181-099002/ES/NIEHS NIH HHS; S11 ES011181-099003/ES/NIEHS NIH HHS; S11 ES11181/ES/NIEHS NIH HHS
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Recombinant Proteins; 0/Xenobiotics; 1W21G5Q4N2/Okadaic Acid; EC protein, human; EC protein, human; EC P-450 CYP3A; EC Phosphatase 2

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