Bile acid toxicity

Bai CL, Stacey NH. 1993. Effects of carbon tetrachloride and chloroform on bile acid transport in isolated rat hepatocytes relationship to elevated serum bile acids. Toxic In Vitro 7(3) 197-203. 

Uppal H, Saini SP, Moschetta A, et al. Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology. 2007 45(2) 422-432. 

Guo, G.L., Lambert, G., Negishi, M. Ward, J.M., Brewer, H.B., fr., Kliewer, S.A. et al. (2003) Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. The Journal of Biological Chemistry, 278 (46), 45062-45071. 

Ursodiol may slow progression of liver disease. It improves bile flow and may displace toxic bile acids that accumulate in a cholestatic liver, stimulate bicarbonate secretion into the bile, offer a cytoprotective effect, and reduce elevated liver tests. Ursodiol is typically dosed at 15 to 20 mg/kg per day in two divided doses and may be rounded to the nearest tablet size.5,7... 

The answer is a. (Hardman, pp 885-8870 Lovastatin should not be used in patients with severe liver disease. With routine use of lovastatin, serum transaminase values may rise, and in such patients the drug may be continued only with great caution. Lovastatin has also been associated with lenticular opacities, and slit-lamp studies should be done before and one year after the start of therapy There is no effect on the otic nerve. The drug is not toxic to the renal system, and reports of bone marrow depression are very rare There is a small incidence of myopathy, and levels of creatinine kinase should be measured when unexplained muscle pain occurs. Combination with cyclosporine or clofibrate has led to myopathy There is no danger in use with bile acid sequestrants. 

PXR has been demonstrated to act as an LCA sensor and plays an essential role in detoxification of cholestatic bile acids [11,61]. Studies in different animal models showed that activation of PXR protected against severe liver damage induced by LCA. Pretreatment of wild-type mice, but not the PXR-null mice, with PCN reduced the toxic effects of LCA. Moreover, genetic activation of PXR by expressing the activated... 

Other Toxicity Concerns. Additional toxicity concerns include interference with normal metabolism and function of mucosal cells, for example, water absorption by these cells [80]. The unconjugated bile acids are known to block amino acid metabolism [81] and glucose transport [82]. There is a possibility of biotransformation of these enhancers to toxic or carcinogenic substances by hepatic monooxygenases [83]. Absorption of permeation enhancers into the systemic circulation can also cause toxicity, for example, azone [84] and hexamethylene lauramide [85] which are absorbed... 

Glutathione S transferases bind bile acids in vitro but doubt has been cast over whether this happens in vivo as these enzymes were not labelled by fluorescently labelled bile acids in experiments to identify the carrier proteins but may play a role with the raised levels in cholestasis. Liver fatty-acid-binding protein has been shown to bind bile acids by using a displacement assay with fluorescent fatty-acid ligand. This work clearly showed displacement to be directly related to hydrophobicity, such that lithocholate conjugates had the greatest effect. This may indicate a mechanism to minimise toxicity within the hepatocyte. 

Figure 2.2 Secretion of bile acids and biliary components. Bile acids (BA) cross the hepatocyte bound to 3a-hydroxysteroid dehydrogenase and are exported into the canaliculus by the bile-salt export protein (BSEP). Phosphatidylcholine (PC) from the inner leaflet of the apical membrane is flipped to the outer layer and interacts with bile acids secreted by BSEP. BA, PC, together with cholesterol from the membrane form mixed micelles that are not toxic to epithelial membranes of the biliary tree. Aquaporins (AQP) secrete water into bile.

D. Nehra, P. Howell, C. P. Williams, J. K. Pye and J. Beynon, Toxic bile acids in gastro-oesophageal reflux disease influence of gastric acidity, Gut, 1999, 44(5), 598. 

Itching associated with retention of bile acids is ameliorated by treatment with the bile acid binding resin cholestyramine. Fat soluble vitamin (A, D and K) deficiency may require administration of supplements. Direct toxic effects of alcohol associated with dietary deficiency may require soluble B vitamin administration. 

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