TY - JOUR T1 - Decreased Bile-Acid Synthesis in Livers of Hepatocyte-Conditional NADPH-Cytochrome-p450 Reductase-Null Mice Results in Increased Bile Acids in Serum JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.114.216796 SP - jpet.114.216796 AU - Xingguo Cheng AU - Youcai Zhang AU - Curtis D. Klaassen Y1 - 2014/01/01 UR - http://jpet.aspetjournals.org/content/early/2014/07/17/jpet.114.216796.abstract N2 - NADPH-cytochrome p450 reductase (Cpr) is essential for the function of microsomal cytochrome p450 mono-oxygenases (Cyp), including those Cyps involved in bile acid (BA) synthesis. Mice with hepatocyte-specific deletion of NADPH-cytochrome p450 reductase (H-Cpr-null) have been established to understand the in vivo function of hepatic Cyps on the metabolism of xenobiotics and endogenous compounds. However, the impact of hepatic Cpr on BA homeostasis is not clear. The present study revealed that H-Cpr-null mice had a 60% decrease of total BA concentration in liver, whereas the total BA concentration in serum was almost doubled. The decreased level of cholic acid (CA) in both serum and livers of H-Cpr-null mice is likely due to diminished enzyme activity of Cyp8b1 that is essential for CA biosynthesis. Feedback mechanisms responsible for the reduced liver BA concentrations and/or increased serum BA concentrations in H-Cpr-null mice included: 1) enhanced alternative BA synthesis pathway, as evidenced by the facts that classical BA synthesis is diminished but chenodeoxycholic acid (CDCA) still increases in both serum and livers of H-Cpr-null mice; 2) inhibition of FXR activation, which increased the mRNA of Cyp7a1 and 8b1; 3) induction of intestinal BA transporters to facilitate BA absorption from intestine to the circulation; 4) induction of hepatic Mrp transporters to increase BA efflux from liver to blood; and 5) increased generation of secondary BAs. In summary, the present study reveals an important contribution of the alternative BA synthesis pathway and BA transporters in regulating BA concentrations in H-Cpr-null mice. ER -