Functional and ultrastructural features of ethanol/bile salts interaction in the isolated perfused rat liver

Abstract

We investigated whether bile salts (BS) with different hydrophobic-hydrophilic properties interact with ethanol on bile secretion, enzyme (aspartate transaminase [AST], lactate dehydrogenase [LDH]) release in the perfusate, liver ultrastructure, and vesicular exocytosis in the isolated perfused rat liver. Ethanol (0.1 or 1%) promoted a rapid decrease of bile flow and BS secretion in livers perfused with taurocholate (TCA), the physiologic BS in the rat (-28% decrease of baseline values with 0.1% and -34% with 1% ethanol). The inhibitory effect of ethanol on bile flow and BS secretion was significantly (P < .02) attenuated by perfusing liver with the hydrophilic BS, tauroursodeoxycholate (TUDCA), and it was exacerbated (P < .02) by perfusion with the hydrophobic BS, taurodeoxycholate (TDCA). The release of AST and LDH in the perfusate was unaffected by 0.1% ethanol, but increased threefold to fivefold by 1% ethanol in TCA-perfused livers. This cytolitic effect of ethanol was not observed in TUDCA-perfused livers, but it was enhanced (P < .03) by perfusion with TDCA. No ultrastructural abnormalities were found in either TCA- or TUDCA-perfused livers, with or without 1% ethanol. Only minimal changes were found in livers perfused with TDCA alone, but, in the presence of TDCA, 1% ethanol induces marked mitochondrial damage. The biliary excretion of the fluid phase marker horseradish peroxidase was inhibited by ethanol, an effect reversed by TUDCA (P < .02) and exacerbated by TDCA (P < .04). In conclusion, this study demonstrates that hydrophilic BS such as TUDCA counteract the inhibitory effect of ethanol on bile secretion and vesicular exocytosis as well as the ethanol-induced cytolitic effect in the isolated perfused rat liver. In the presence of hydrophobic BS such as TDCA, the exposure to ethanol promotes a marked inhibition of bile secretion and vesicular exocytosis as well as prominent mitochondrial damage.

Bile Salts Modulate Chronic Ethanol-Induced Hepatotoxicity

“…This UDC beneficial effect may be due to the slightly decreased hydrophobicity index of the bile salt pool, and more specifically to the greater capacity of UDC to protect hepatocytes, than the other two hydrophilic bile acids, cholic and βMC. Our data confirm and extend previous findings (Alvaro et al, 1995;Neuman et al, 1995;Oliva et al, 1998) on the hepatoprotective effect of UDC. A key point of the present study is that UDC attenuates cytotoxicity of ethanol plus CDC co-administration.…”

“…On the other hand, UDC has been shown to improve liverfunction tests in patients with alcoholic cirrhosis and cholestasis who still continue to consume ethanol (Plevris et al, 1991). Moreover, UDC protects Hep G2 cells from ethanol-induced cytotoxicity (Neuman et al, 1995) and, similarly, tauroursodeoxycholate (TUDC) counteracts the inhibitory effect of ethanol on bile secretion and vesicular exocytosis in the isolated perfused rat liver (Alvaro et al, 1995). We have recently demonstrated that UDC was able to reduce steatosis and lipid peroxidation induced by chronic ethanol feeding in rats (Oliva et al, 1998;Tabouy et al, 1998).…”

On the Mechanisms of Biliary Flux

“…It was recognized early on that the osmotic coefficient of a particular BA does not necessarily correlate with its choleretic potential. ( 12 ) BAs are hydrophobic molecules that undergo a phase transition to form micelles at concentrations exceeding their critical micellar concentrations (CMCs). These micellar suspensions have a much lower osmolarity than dilute solutions of Bas.…”

Bile Acid Therapy in Pediatric Hepatobiliary Disease: The Role of Ursodeoxycholic Acid

“…Elucidation of the potential cellular mechanisms of bile acid‐induced liver injury has allowed the development of therapeutic strategies for the treatment of cholestasis (19‐40,41‐62) (Table 1). The rationale for the use of UDCA in liver disease is based on the hypothesis that intracellular accumulation of toxic, endogenous bile acids leads to hepatobiliary injury (12,63‐65).…”

“…The degree of cytotoxicity of a given bile acid is influenced by the chemical structure and the degree of hydrophobicity (66‐68). Endogenous dihydroxy (CDCA) or monohydroxy (LA) bile acids are cytotoxic and cholestatic when parenterally administered to rodents, delivered to isolated perfused livers, or incubated with isolated hepatocytes (19‐21,69). During chronic administration to animals, bile acids can induce bile duct injury and ductular proliferation, as well as fibrosis and cirrhosis (15).…”