Document Detail


Biotransformation of lithocholic acid by rat hepatic microsomes: metabolite analysis by liquid chromatography/mass spectrometry.
MedLine Citation:
PMID:  18039809     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Lithocholic acid is a lipid-soluble hepatotoxic bile acid that accumulates in the liver during cholestasis. A potential detoxification pathway for lithocholic acid involves hydroxylation by hepatic cytochrome P450 (P450) enzymes. The purpose of the present study was to identify the hepatic microsomal metabolites of lithocholic acid by liquid chromatography/mass spectrometry and to determine the P450 enzymes involved. Incubation of lithocholic acid with rat hepatic microsomes and NADPH produced murideoxycholic acid (MDCA), isolithocholic acid (ILCA), and 3-keto-5beta-cholanic acid (3KCA) as major metabolites and 6-ketolithocholic acid and ursodeoxycholic acid as minor metabolites. Experiments with hepatic microsomes prepared from rats pretreated with P450 inducers and with inhibitory antibodies indicated that CYP2C and CYP3A enzymes contribute to microsomal MDCA formation. Results obtained with a panel of recombinant P450 enzymes and CYP2D6 antiserum showed that CYP2D1 can also catalyze MDCA formation. Similar experimental evidence revealed that formation of 3KCA was mediated primarily by CYP3A enzymes. ILCA formation appeared to be catalyzed by a distinct pathway mediated largely by microsomal non-P450 enzymes. Based on the results obtained using lithocholic acid and 3KCA as substrates, a mechanism for the formation of ILCA involving a geminal diol intermediate is outlined. In conclusion, lithocholic acid was extensively metabolized by multiple P450 enzymes with the predominant biotransformation pathway being hydroxylation at the 6beta-position. This study provides an insight into possible routes of detoxification of lithocholic acid.
Authors:
Anand K Deo; Stelvio M Bandiera
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-11-26
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  36     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-25     Completed Date:  2008-02-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  442-51     Citation Subset:  IM    
Affiliation:
Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biotransformation
Chromatography, Liquid
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  metabolism*
Female
Lithocholic Acid / metabolism*
Male
Mass Spectrometry
Microsomes, Liver / metabolism*
Rats
Rats, Long-Evans
Rats, Sprague-Dawley
Rats, Wistar
Recombinant Proteins / antagonists & inhibitors,  metabolism
Chemical
Reg. No./Substance:
0/Recombinant Proteins; 434-13-9/Lithocholic Acid; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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