Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice.

Efficient detoxification of bile acids is necessary to avoid pathological conditions such as cholestatic liver damage and colon cancer. The orphan nuclear receptors PXR and CAR have been proposed to play an important role in the detoxification of xeno- and endo-biotics by regulating the expression of detoxifying enzymes and transporters. In this report, we showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-sensitive manner. A regimen of lithocholic acid treatment, which was tolerated by wild-type and PXR null mice, caused a marked accumulation of serum bile acids and histological liver damage as well as an increased hepatic lipid deposition in double knockout males. The increased sensitivity in males was associated with genotype-specific suppression of bile acid transporters and loss of bile acid-mediated downregulation of small heterodimer partner, whereas the transporter suppression was modest or absent in females. The double knockout mice also exhibited gene- and tissue-specific dysregulation of PXR and CAR target genes in response to PXR and CAR agonists. In conclusion, althoughthe cross-regulation of target genes by PXR and CAR has b een proposed, the current study represents in vivo evidence of the combined loss of both receptors causing a unique pattern of gene regulation that can be translated into physiological events such as sensitivity to toxic bile acids.

Effect of biliary stasis and hepatotoxins on the excretion of iopanoate in the rat.

In rats, hepatic dysfunction was induced with CCl4, SKF 525-A, taurolithocholic acid and alpha-naphthylisothiocyanate and by acute and chronic surgical ligation of the bile duct. Biliary and urinary excretion of 125I-labeled iopanoate was measured after a standard i.v. dose. In the absence of normal biliary excretion, the amount excreted in the urine varied over a wide range (0.25-11.2 percent of the dose), with highest rates of urinary excretion occurring after alpha-naphthylisothiocyanate and chronic stasis. Drug disposition was further determined by tissue analysis of liver and kidney. The results indicate that, for a drug that is normally almost exclusively excreted by the bile, in the presence of hepatic dysfunction the amount excreted by the alternate urinary route depends on the type of the induced hepatic disorder. The intrarenal distribution of 125I-radioactivity is strongly influenced by its plasma concentration rather than just by the rate of excretion in the urine.