Cholestasis bile adds

Intracellular accumulation of bile adds continues to maintain the state of cholestasis. Bile acids are detergents that cause damage to biomembranes. 

In each form of cholestasis, atypical bile adds, such as monohydroxy bile acids, aUo-bile adds, 1- or 6-hydroxylated bile acids and their sulphated or glucuronidated derivatives, are found in the sermn and/or urine. In cholestasis, the increase in the neosynthesis of atypical bile adds that pass into the kidney can be seen as a compensatory mechanism which eliminates potentially hepatotoxic bile acids by renal clearance. The highest renal excretion quota is demonstrated by tetrahydroxy bile acids. 

Several experimental systems to check the inhibition potency of bile add transport have been characterized. Using sandwich-cultured human hepatocytes, bosentan, cyclosporin A, CI-1034 (endothelin-A receptor antagonist), glyburide, erythromycin estolate, and troleandomycin could inhibit the taurocholate efflux to the bile pocket [234]. Moreover, Mita et al. [235] construded NTCP/BSEP double-transfeded cells and some cholestasis-induced compounds inhibited both the NTCP-mediated uptake and the BSEP-mediated efflux of taurocholate. Then, they have found fluorescent bile acids whose transcellular transport was dearly observed, which may be used for the rapid identification of inhibitors of NTCP and BSEP in drug screening process [235]. 

Bile acids are the end products of hepatic cholesterol catabolism and play essential roles in eliminating cholesterol from the body. However, pathophysiological accumulation of bile acids elicits cytotoxicity and can lead to cholestasis in livers. PXR plays a critical role in bile acid detoxification, by regulating bile add biosynthesis, transport and metaboUsm. Stndies in PXR knock out and humanized PXR mice revealed that PXR reduces secondary bile acid lithocholic add (LCA)-induced liver toxidty [77], PXR regulates... 

Mita, S. et al. (2006) Inhibition ofbile add transport across Na + /taurocholate cotransporting polypeptide (SLClOAl) and bile salt export pump (ABCB 11)-coexpressing LLC-PKl cells by cholestasis-inducing drugs. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34 (9), 1575-1581. 

Monohydroxy bile acids (such as lithocholic acid produced in the intestine) are deemed to be cholestatic factors. They can, however, also be generated in the liver as a result of damage to the smooth endoplasmic reticulmn, with a decrease in activity of cytochrome P 450-dependent 7a-hydroxylase in cases of cholestasis, 3p-hydroxy-5S-cholic add is formed from cholesterol and converted into lithocholic acid and aUo-lithocholic acid (so-called foetal metabolic pathway of bile acids). (10)... 

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