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Drug Metabolism and Disposition Fast Forward
First published on June 26, 2008; DOI: 10.1124/dmd.108.022194

0090-9556/08/3610-1983-1991$20.00
DMD 36:1983-1991, 2008

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Identification of Human Hepatic Cytochrome P450 Enzymes Involved in the Biotransformation of Cholic and Chenodeoxycholic Acid

Anand K. Deo, and Stelvio M. Bandiera

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada

3{alpha},7{alpha},12{alpha}-Trihydroxy-5β-cholan-24-oic (cholic) and 3{alpha},7{alpha}-dihydroxy-5β-cholan-24-oic (chenodeoxycholic) acids are the predominant hepatic and biliary bile acids of most mammalian species including humans. Cholic and chenodeoxycholic acids are synthesized from cholesterol and accumulate in the liver during cholestasis. Biotransformation by hepatic cytochrome P450 (P450) enzymes represents a potentially effective pathway for elimination of these lipid-soluble bile acids. We developed a liquid chromatography/mass spectrometry-based assay to identify and quantify the human hepatic microsomal metabolites of cholic acid and chenodeoxycholic acid, and using a panel of human recombinant P450 enzymes, we determined the P450 enzymes involved. Incubation of cholic acid with human hepatic microsomes and NADPH produced a single metabolite, 7{alpha},12{alpha}-dihydroxy-3-oxo-5β-cholan-24-oic (3-dehydrocholic) acid. Of the recombinant P450 enzymes tested, only CYP3A4 catalyzed 3-dehydrocholic acid formation. Similar experiments with chenodeoxycholic acid revealed the formation of 7{alpha}-hydroxy-3-oxo-5β-cholan-24-oic acid and 3{alpha},6{alpha},7{alpha}-trihydroxy-5β-cholan-24-oic ({gamma}-muricholic) acid as major metabolites and 3{alpha}-hydroxy-7-oxo-5β-cholan-24-oic (7-ketolithocholic) acid and cholic acid as minor metabolites. Among the human recombinant P450 enzymes examined, CYP3A4 exhibited the highest rates of formation for 7{alpha}-hydroxy-3-oxo-5β-cholan-24-oic acid and {gamma}-muricholic acid from chenodeoxycholic acid. Formation of 7-ketolithocholic acid and cholic acid from chenodeoxycholic acid has not been reported previously and could not be attributed to any of the recombinant P450 enzymes tested. In conclusion, the predominant pathway for the biotransformation of both cholic and chenodeoxycholic acids in human hepatic microsomes was oxidation at the third carbon of the cholestane ring. This study highlights a major role for CYP3A4 and suggests a possible route for the elimination of these two bile acids.

Address correspondence to: Stelvio M. Bandiera, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, Canada V6T 1Z3. E-mail: bandiera{at}interchange.ubc.ca




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Ligand Diversity of Human and Chimpanzee CYP3A4: Activation of Human CYP3A4 by Lithocholic Acid Results from Positive Selection
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[Abstract] [Full Text] [PDF]


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