Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans

Shogo Takahashi, Tatsuki Fukami, Yusuke Masuo, Chad N. Brocker, Cen Xie, Kristopher W. Krausz, C. Roland Wolf, Colin J. Henderson, Frank J. Gonzalez (Lead / Corresponding author)

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    Abstract

    Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYP)s and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6-position to form α-muricholic acid (α-MCA), and ursodeoxycholic acid (UDCA) to form β-muricholic acid (-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 acids analysis further revealed the absence of MCA and their conjugated-derivatives, and high concentration of CDCA, 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. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, thus indicating that human CYP2C9 does not oxidize CDCA and UDCA thus explaining the species differences in production of MCA. Since humans do not produce MCA, they lack taurine-β-MCA, a farnesoid X receptor (FXR) antagonists in mouse, that modulates obesity, insulin resistance and hepatosteatosis.

    Original languageEnglish
    Pages (from-to)2130-2037
    Number of pages8
    JournalJournal of Lipid Research
    Volume57
    Early online date16 Sep 2016
    DOIs
    Publication statusPublished - Dec 2016

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    Keywords

    • chenodeoxycholic acid
    • cytochrome P450
    • Cyp2c70
    • enzyme kinetics
    • liver
    • muricholic acid
    • ursodeoxycholic acid

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