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

    Fingerprint

    Chenodeoxycholic Acid
    Ursodeoxycholic Acid
    Bile Acids and Salts
    Metabolism
    Taurine
    Liver
    Oxidation
    Glucuronic Acid
    Metabolites
    Glycine
    Cytochrome P-450 Enzyme System
    Sulfates
    Rats
    Cholesterol
    Insulin
    Derivatives
    Cecum
    Biotransformation
    Feces
    Insulin Resistance

    Keywords

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

    Cite this

    Takahashi, S., Fukami, T., Masuo, Y., Brocker, C. N., Xie, C., Krausz, K. W., ... Gonzalez, F. J. (2016). Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. Journal of Lipid Research, 57, 2130-2037. https://doi.org/10.1194/jlr.M071183
    Takahashi, Shogo ; Fukami, Tatsuki ; Masuo, Yusuke ; Brocker, Chad N. ; Xie, Cen ; Krausz, Kristopher W. ; Wolf, C. Roland ; Henderson, Colin J. ; Gonzalez, Frank J. / Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. In: Journal of Lipid Research. 2016 ; Vol. 57. pp. 2130-2037.
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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.",
    keywords = "chenodeoxycholic acid, cytochrome P450, Cyp2c70, enzyme kinetics, liver, muricholic acid, ursodeoxycholic acid",
    author = "Shogo Takahashi and Tatsuki Fukami and Yusuke Masuo and Brocker, {Chad N.} and Cen Xie and Krausz, {Kristopher W.} and Wolf, {C. Roland} and Henderson, {Colin J.} and Gonzalez, {Frank J.}",
    note = "This work was supported by the National Cancer Institute Intramural Research Program, Center for Cancer Research, and National Institutes of Health Grant U54 ES16015 (F.J.G), and a Programme Grant support from Cancer Research UK, C4639/A10822 to C.R.W. S.T. was supported by a Japanese Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (KAITOKU-NIH). T.F. and Y.M. were supported by a program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2601) from the Japanese Society for the Promotion of Sciences.",
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    Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. / Takahashi, Shogo; Fukami, Tatsuki; Masuo, Yusuke; Brocker, Chad N.; Xie, Cen; Krausz, Kristopher W.; Wolf, C. Roland; Henderson, Colin J.; Gonzalez, Frank J. (Lead / Corresponding author).

    In: Journal of Lipid Research, Vol. 57, 12.2016, p. 2130-2037.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans

    AU - Takahashi, Shogo

    AU - Fukami, Tatsuki

    AU - Masuo, Yusuke

    AU - Brocker, Chad N.

    AU - Xie, Cen

    AU - Krausz, Kristopher W.

    AU - Wolf, C. Roland

    AU - Henderson, Colin J.

    AU - Gonzalez, Frank J.

    N1 - This work was supported by the National Cancer Institute Intramural Research Program, Center for Cancer Research, and National Institutes of Health Grant U54 ES16015 (F.J.G), and a Programme Grant support from Cancer Research UK, C4639/A10822 to C.R.W. S.T. was supported by a Japanese Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health (KAITOKU-NIH). T.F. and Y.M. were supported by a program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2601) from the Japanese Society for the Promotion of Sciences.

    PY - 2016/12

    Y1 - 2016/12

    N2 - 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.

    AB - 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.

    KW - chenodeoxycholic acid

    KW - cytochrome P450

    KW - Cyp2c70

    KW - enzyme kinetics

    KW - liver

    KW - muricholic acid

    KW - ursodeoxycholic acid

    U2 - 10.1194/jlr.M071183

    DO - 10.1194/jlr.M071183

    M3 - Article

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    VL - 57

    SP - 2130

    EP - 2037

    JO - Journal of Lipid Research

    JF - Journal of Lipid Research

    SN - 0022-2275

    ER -