Lithocholic acid

Lithocholic acid (LCA) is a hydrophobic secondary bile acid that is primarily formed in the intestine by the bacterial 7α-dehydroxylation of chenodeoxycholic acid. LCA causes intrahepatic cholestasis (cessation or impairment of bile flow). LCA activates PXR (pregnane X receptor), and the LCA-induced severe liver damage can be protected by the activation of PXR. ^[1] LCA can activate farnesoid X receptor (FXR) with EC50 of 3.8 μM. ^[2] LCA directly binds VDR (vitamin D receptor) with K_i of 29μM, activates VDR (vitamin D receptor) 30 μM, with much more sensitivity than the other nuclear receptors (eg. PXR, FXR), and its toxic effect is thus protected. ^[3] LCA has tumor-promoting activity, inhibits mammalian DNA Polymerase β with IC50 of 15 μM. ^[4]

Administration of LCA and its conjugates to rodents causes intrahepatic cholestasis,a pathogenic state characterized by decreased bile flow and the accumulation of bile constituents in the liver and blood. ^[1] In DMH (dimethyldydrazine)-induced murine carcinogenesis model, LCA suppresses apoptosis almost completely in premalignant colon. ^[5] LCA activates VDR, induces expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. ^[3]

• Competitive ligand binding assay.

  Ligand binding is performed using lysates from COS-7 cells transfected with expression plasmids for VDR or RXRα. Binding is performed overnight at 4°C in lysate buffer with 0.71 nM (18 Ci/mmol) [³H]1,25(OH)₂D₃ and bile acid competitor. Unbound [³H]1,25(OH)₂D₃ is removed by adsorption to dextran-coated charcoal and the supernatant removed for scintillation counting. K_i values are calculated from a computer fit of competition curves from triplicate assays.

• Animal Models

  Mouse

• Dosages

  0.125 mg/g, twice a day for 4 days.

• Administration

  i.p.