| The algal hepatoxoxin okadaic acid is a substrate for human cytochromes CYP3A4 and CYP3A5. | |
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MedLine Citation:
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PMID: 19699225 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Fujiang Guo; Tianying An; Kathleen S Rein |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2009-08-20 |
Journal Detail:
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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:
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Created Date: 2010-01-29 Completed Date: 2010-04-08 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 1307333 Medline TA: Toxicon Country: England |
Other Details:
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Languages: eng Pagination: 325-32 Citation Subset: IM |
Copyright Information:
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Copyright 2009 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Biotransformation Chromatography, High Pressure Liquid Chromatography, Ion Exchange Cytochrome P-450 CYP3A / antagonists & inhibitors, metabolism* Drug-Induced Liver Injury / enzymology* Enzyme Inhibitors / metabolism*, pharmacology Humans Kinetics Liver / enzymology Mass Spectrometry Microsomes, Liver / enzymology Okadaic Acid / metabolism*, pharmacology Oxidation-Reduction Protein Phosphatase 2 / antagonists & inhibitors Recombinant Proteins / metabolism Spectrometry, Mass, Electrospray Ionization Xenobiotics / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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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 ES011181-06/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 |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Recombinant Proteins; 0/Xenobiotics; 78111-17-8/Okadaic Acid; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/CYP3A5 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; EC 3.1.3.16/Protein Phosphatase 2 |
| Comments/Corrections | |
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