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

• Published in: Journal of lipid research Vol. 57; no. 12; pp. 2130 - 2137
• Main Authors: Takahashi, Shogo, Fukami, Tatsuki, Masuo, Yusuke, Brocker, Chad N., Xie, Cen, Krausz, Kristopher W., Wolf, C. Roland, Henderson, Colin J., Gonzalez, Frank J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; chenodeoxycholic acid; Cholic Acids - biosynthesis; Cyp2c70; Cytochrome P-450 Enzyme System - physiology; cytochrome P450; enzyme kinetics; Gene Expression; Hep G2 Cells; Humans; Kinetics; liver; Liver - enzymology; Male; Mice, Inbred C57BL; Mice, Knockout; muricholic acid; Oxidation-Reduction; Species Specificity; ursodeoxycholic acid; ursodeoxycholic acid; liver; Cyp2c70; cytochrome P450; muricholic acid; chenodeoxycholic acid; enzyme kinetics
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M071183

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.