title: Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans.
abstract: Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYPs) and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6β-position to form α-muricholic acid (MCA) and ursodeoxycholic acid (UDCA) to form β-MCA. However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that α-MCA and β-MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acid analysis further revealed the absence of MCAs and their conjugated derivatives, and high concentrations of CDCA and UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that α-MCA and β-MCA were produced by oxidation of CDCA and UDCA by Cyp2c70, respectively. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA, thus explaining the species differences in production of MCA. Because humans do not produce MCA, they lack tauro-β-MCA, a farnesoid X receptor antagonist in mouse that modulates obesity, insulin resistance, and hepatosteatosis.
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Shogo
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Masuo
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Chad N
authors.initials: CN
authors.lastname: Brocker
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Cen
authors.initials: C
authors.lastname: Xie
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Division of Cancer, School of Medicine, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, United Kingdom.
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
authors.affiliation: Division of Cancer, School of Medicine, Jacqui Wood Cancer Centre, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Henderson
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Electronic address: gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D002793:Cholic Acids / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D015870:Gene Expression; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D013045:Species Specificity
chemical_list: D002793:Cholic Acids; C004821:muricholic acid; D003577:Cytochrome P-450 Enzyme System; C000621935:cytochrome P-450 2C70, mouse
keywords: Cyp2c70; chenodeoxycholic acid; cytochrome P450; enzyme kinetics; liver; muricholic acid; ursodeoxycholic acid