Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450.

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Schuetz EG, Strom S, Yasuda K, Lecureur V, Assem M, Brimer C, Lamba J, Kim RB, Ramachandran V, Komoroski BJ, Venkataramanan R, Cai H, Sinal CJ, Gonzalez FJ, Schuetz JD

Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450.

J Biol Chem. 2001 Oct 19;276(42):39411-8. doi: 10.1074/jbc.M106340200. Epub 2001 Aug 16.

PubMed ID

11509573 [ View in PubMed

]

Abstract

Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy of bile acids as ligands for the farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile acid transcriptional activation of the mouse and human BSEP/SPGP promoters. In FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Notably, the rank order of bile acids as CYP3A4 inducers and activators of pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely paralleled each other but was markedly different from their hierarchy and potency as inducers of BSEP in human hepatocytes. Moreover, the hepatoprotective bile acid ursodeoxycholic acid, which reverses hydrophobic bile acid hepatotoxicity, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing enzyme) in primary human hepatocytes thus providing one mechanism for its hepatoprotection. Because serum and urinary bile acids increased in FXR/BAR -/- mice, we evaluated hepatic transporters for compensatory changes that might circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-regulation. In contrast, MRP4 was substantially increased in the FXR/BAR nullizygous mice and was further elevated by cholic acid. Thus, enhanced hepatocellular concentrations of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consistent with activation of PXR/SXR by bile acids.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Deoxycholic acid	Bile salt export pump	Protein	Humans	Unknown	Inducer	Details
Ursodeoxycholic acid	Bile salt export pump	Protein	Humans	Unknown	Substrate Inhibitor Inducer	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
Atazanavir Deoxycholic acid	Deoxycholic acid may increase the excretion rate of Atazanavir which could result in a lower serum level and potentially a reduction in efficacy.
Atazanavir Taurocholic acid	Taurocholic acid may increase the excretion rate of Atazanavir which could result in a lower serum level and potentially a reduction in efficacy.
Atenolol Dexamethasone	Dexamethasone may increase the excretion rate of Atenolol which could result in a lower serum level and potentially a reduction in efficacy.
Atenolol Deoxycholic acid	Deoxycholic acid may increase the excretion rate of Atenolol which could result in a lower serum level and potentially a reduction in efficacy.
Atenolol Taurocholic acid	Taurocholic acid may increase the excretion rate of Atenolol which could result in a lower serum level and potentially a reduction in efficacy.