Effects of ursodeoxycholic acid and chenodeoxycholic acid on human hepatocytes in primary culture

Abstract

Hepatic bile acid concentrations are elevated in chronic cholestasis because of reduced canalicular excretion and active ileal absorption of the fraction eliminated in the gut. Ursodeoxycholic acid (UDCA) reduces the intestinal absorption of endogenous bile acids, thereby diminishing the concentrations to which liver cells are exposed. In the isolated perfused liver (in which vectorial bile acid transport is maintained), UDCA reduces the cytotoxic and cholestatic effects of endogenous bile acids. As a result, it has been suggested that UDCA or one of its conjugates could have a direct protective effect on hepatocyte structure and function. We therefore studied the effects of chenodeoxycholic acid (CDCA) and tauroursodeoxycholic acid (TUDCA) alone and in combination on the viability and certain functions of human hepatocytes in primary culture. TUDCA did not affect intracellular concentrations of CDCA when added concomitantly. In other experiments, CDCA (100 to 500 mumol/L) induced concentration-dependent increases in lactate dehydrogenase (LDH) leakage and decreases in cellular protein synthesis and albumin secretion. Neither TUDCA nor UDCA had similar effects at the same concentrations, nor did they have a protective effect when added concomitantly with CDCA at equimolar or twice-equimolar concentrations. These results suggest that UDCA has no direct cytoprotective effect when the bile acid concentrations to which human hepatocytes are exposed are unchanged. They also suggest that the hepatoprotective effect of UDCA in cholestatic human liver diseases and in the isolated perfused liver loaded with hydrophobic bile acids occurs through its effect on intestinal and hepatocyte transport systems.

Taurohyodeoxycholic acid protects against taurochenodeoxycholic acid-induced cholestasis in the rat

“…Moreover, it has been recently reported that, in cultured human hepatocytes, UDCA has no direct cytoprotective effect, which further supports that its effect is on the hepatocyte transport system. 23 The most particular effect of THDCA was the selective increase in PL secretion, even during coinfusion with TCDCA; the hepatic bile produced was more enriched in PL as compared with TUDCA or the saline control (P Ͻ .001).…”

Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis

“…More hydrophobic bile acids (CA, CDCA, DCA) rapidly induce apoptosis, whereas less hydrophobic bile acids (UDCA) are less toxic . Moreover, total plasma bile acids and primary plasma bile acids (CA and CDCA) levels have been shown to positively correlated with the AH severity and steatosis .…”

Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha

“…Previous studies have emphasized the cytoprotective effects of TUDCA in hepatocytes as the primary therapeutic mechanism in chronic liver disease. 44,45 The proliferating cholangiocytes may be an important promoter for liver injury after BDL 46,47 and play a role in the progression of chronic cholestatic liver diseases such as PBC. Because proliferating cholangiocytes release proinflammatory cytokines, 46,47 inhibition of cholangiocyte proliferation by UDCA and TUDCA may reduce cytokineinduced hepatic inflammation and fibrosis.…”