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First published on November 26, 2007; DOI: 10.1124/dmd.107.017533

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Received for publication July 9, 2007.
Revised November 13, 2007.
Accepted for publication November 14, 2007.

BIOTRANSFORMATION OF LITHOCHOLIC ACID BY RAT HEPATIC MICROSOMES: METABOLITE ANALYSIS BY LC/MS

Anand K Deo 1 Stelvio M Bandiera 1*

1 University of British Columbia

* Address correspondence to: E-mail: bandiera{at}interchange.ubc.ca

Abstract

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 (CYP) 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 CYP enzymes involved. Incubation of lithocholic acid with rat hepatic microsomes and NADPH produced murideoxycholic acid (MDCA), isolithocholic acid (ILCA) and 3-keto-5{beta}-cholanic acid (3KCA) as major metabolites, and 6-ketolithocholic acid (6KLCA) and ursodeoxycholic acid (UDCA) as minor metabolites. Experiments with hepatic microsomes prepared from rats pretreated with CYP inducers and with inhibitory antibodies indicated that CYP2C and CYP3A enzymes contribute to microsomal MDCA formation, while results obtained with a panel of recombinant CYP 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-CYP enzymes. On the basis of 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 CYP enzymes with the predominant biotransformation pathway being hydroxylation at the 6{beta}-position. This study provides an insight into possible routes of detoxification of lithocholic acid.


Key words: bile acid metabolism, cytochrome P450, enzyme kinetics, metabolite identification, microsomes


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