| Human CYP2C9 and CYP2A6 mediate formation of the hepatotoxin 4-ene-valproic acid. | |
| | |
MedLine Citation:
|
PMID: 9353388 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Cytochrome P450-dependent desaturation of the anticonvulsant drug valproic acid (VPA) results in formation of the hepatotoxin, 4-ene-VPA. Polytherapy with other anticonvulsants which are known P450 inducers increases the flux through this bioactivation pathway. The aim of the present study was to identify specific, inducible forms of human liver P450 which catalyze terminal desaturation of VPA. Oxidized VPA metabolites formed in an NADPH-dependent manner by human liver microsomes were quantified by gas-chromatography/mass spectrometry. In vitro reaction conditions were established which reflected the product profile found in vivo. Production of 4-ene-VPA by microsomal P450s could be inhibited significantly by coumarin, sulfaphenazole and diethyldithiocarbamate, but not by triacetyloleandomycin, quinidine or furafylline. Recombinant human CYP3A4 did not form detectable levels of 4-ene-VPA and, of nine additional isoforms expressed in either HepG2 or lymphoblastoid cells which were screened for VPA desaturase activity, only CYP2C9 and CYP2A6 formed detectable levels of metabolite. Consequently, CYP3A4, the isoform usually associated with induction by anticonvulsants cannot be responsible for the enhanced 4-ene-VPA formation that occurs during polytherapy. Instead, enhanced activity in vivo likely results from induction of CYP2A6 and/or CYP2C9. |
| | |
Authors:
|
A J Sadeque; M B Fisher; K R Korzekwa; F J Gonzalez; A E Rettie |
Related Documents
:
|
20599868 - Effect of valproic acid treatment on copper availability in adult epileptic patients. 9920148 - Effect of long-term valproic acid administration on the efficiency of carnitine reabsor... 8819478 - The mitochondrial permeability transition: a new pathophysiological mechanism for reye'... 15349008 - Valproic acid-induced hyperammonemia: a case report. 18646748 - Rapid synthesis of polyethylenimine-protected prussian blue nanocubes through a thermal... 16347458 - Role of amino acids and vitamins in nutrition of mesophilic methanococcus spp. |
Publication Detail:
|
Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
|
Title: The Journal of pharmacology and experimental therapeutics Volume: 283 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 1997 Nov |
Date Detail:
|
Created Date: 1997-12-08 Completed Date: 1997-12-08 Revised Date: 2007-11-14 |
Medline Journal Info:
|
Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
|
Languages: eng Pagination: 698-703 Citation Subset: IM |
Affiliation:
|
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adolescent Adult Anticonvulsants / metabolism* Aryl Hydrocarbon Hydroxylases* Child Cytochrome P-450 Enzyme System / physiology* Fatty Acids, Monounsaturated / metabolism*, toxicity Female Humans Liver / drug effects*, metabolism Male Middle Aged Mixed Function Oxygenases / physiology* Steroid 16-alpha-Hydroxylase* Steroid Hydroxylases / physiology* Valproic Acid / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
|
GM07750/GM/NIGMS NIH HHS; GM32165/GM/NIGMS NIH HHS; GM49054/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Anticonvulsants; 0/Fatty Acids, Monounsaturated; 1575-72-0/2-propyl-4-pentenoic acid; 9035-51-2/Cytochrome P-450 Enzyme System; 99-66-1/Valproic Acid; EC 1.-/Mixed Function Oxygenases; EC 1.14.-/Steroid Hydroxylases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C9 protein, human; EC 1.14.14.1/Steroid 16-alpha-Hydroxylase; EC 1.14.14.1/coumarin 7-hydroxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Peptide YY inhibits intestinal Cl- secretion in experimental porcine cryptosporidiosis through a pro...
Next Document: Desensitization of a gamma-aminobutyric acid type A receptor in rat is increased by chronic treatmen...