EXTRAHEPATIC DEPOSITION AND CYTOTOXICITY OF LITHOCHOLIC ACID - STUDIES IN 2 HAMSTER MODELS OF HEPATIC-FAILURE AND IN CULTURED HUMAN FIBROBLASTS

Effects of bile acids ore tissues outside of the enterohepatic circula tion may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary d isease. Two hamster models of hepatic failure, namely functional hepat ectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation t o various experimental conditions, such as binding of LCA to low-densi ty lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes a fter iv infusion of [24-C-14]LCA, the majority of LCA in sham-operated control animals was recovered in liver, bile, and small intestine. Af ter hepatectomy, a significant increase in LCA was found in blood, mus cle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a grea ter than twofold increase in LCA was observed in the colon. In the hep atectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin. The comparative time- and concentration-dependent uptake of [C-14]LCA, [C-14]chenodeo xycholic acid (CDCA), and [C-14]cholic acid (CA) in cultured human fib roblasts was nonsaturable and remained a function of concentration, In itial rates of uptake were significantly increased by approximately te nfold, with decreasing hydroxylation of the respective bile acid. Afte r 1 hour of exposure of fibroblasts to LCA, there was a significant, d ose-dependent decrease in mitochondrial dehydrogenase activity from 18 % to 34% of the control, at LCA concentrations ranging from 1 to 20 mu mol/L. At a respective concentration of 100 and 700 mu mol/L, CDCA ca used a 35% and 99% inhibition of mitochondrial dehydrogenase activity. None of the bile acids tested, with the exception of 700 mu mol/L CDC A, caused a significant release of cytosolic lactate dehydrogenase int o the medium, In conclusion, we show that bile acids selectively accum ulate in nonhepatic tissues under two conditions of impaired liver fun ction. Furthermore, the extrahepatic tissue distribution of bile acids during cholestasis may be affected by serum lipoprotein composition. At a respective concentration of 1 and 100 mu mol/L, LCA and CDCA indu ced mitochondrial damage in human fibroblasts, after just 1 hour of ex posure. Therefore, enhanced extrahepatic uptake of hydrophobic bile ac ids during liver dysfunction, or disorders of lipoprotein metabolism, may have important implications for bile-acid induced cytotoxic effect s in tissues of the systemic circulation.