Disease relevance of LITHOCHOLIC ACID

• Sulfation of lithocholate as a possible modifier of chenodeoxycholic acid-induced elevations of serum transaminase in patients with gallstones [1].
• In a separate group of 9 cirrhotic patients, fecal bile acid analysis indicated that cirrhotic patients had a significantly lower percentage of deoxycholic acid than 12 patients without liver disease; there was no significant difference in fecal lithocholic acid [2].
• Lithocholate cholestasis--sulfated glycolithocholate-induced intrahepatic cholestasis in rats [3].
• Despite the hepatotoxic effects observed in nonhuman primates, we have found no evidence so far to implicate lithocholate as an etiologic factor in inflammatory bowel disease and hepatic dysfunction nor have we detected other potentially hepatotoxic bile acids in these patients [4].
• Radioactive LCA was administered to squirrel monkeys with biliary fistula [5].

High impact information on LITHOCHOLIC ACID

• Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor [6].
• Further hydroxylation products of lithocholic and chenodeoxycholic acids lost 3H at the same rate, whereas 3H loss from lithocholic acid rapidly ceased, which suggests compartmentation of this bile acid in hepatocytes [7].
• 3 alpha-HSD activity copurified with lithocholic acid-binding activity after sequential gel filtration, chromatofocusing, and affinity chromatography [8].
• The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid and the activity of colonic mucosal ornithine decarboxylase activity were higher in animals fed the 23.5% corn oil or lard diet during the postinitiation compared to the levels in animals fed the 5% corn oil or lard diet [9].
• Dietary wheat bran decreased the concentrations of fecal deoxycholic acid, lithocholic acid, 12-ketolithocholic acid, and neutral sterols and the activities of all bacterial enzymes [10].

Chemical compound and disease context of LITHOCHOLIC ACID

• Because defective sulfation in the nonhuman primate which allows lithocholate to accumulate in the enterohepatic circulation is thought to be responsible for inducing liver damage and because secondary bile acids are reduced after colectomy and in established liver disease, we examined thae capacity of all patients to sulfate labeled lithocholate [4].
• However, even after the onset of lithocholic acid glucuronide-induced cholestasis, little of the administered material was recovered in urine [11].
• In the taurine-deficient rat, the feeding of lithocholate leads to formation of gallstones which contain a mixture of calcium lithocholyl glycine and 3 alpha, 6 beta-dihydroxy cholanoyl glycine [12].
• Serum cholylglycine, sulfated lithocholate conjugates, and bilirubin were significantly higher and the mean duration of symptomatic primary biliary cirrhosis was significantly longer (6.6 vs 2.3 years) in the vitamin E-deficient compared to the vitamin E-sufficient Group A patients [13].
• 1. Using a human hepatoma (Hep G2) cell line that continually synthesizes 3 beta-hydroxy-5-cholenoic acid, lithocholic acid, chenodeoxycholic acid and cholic acid we have determined the metabolism and biological effects of 26-hydroxycholesterol and 7 alpha-hydroxycholesterol [14].

Biological context of LITHOCHOLIC ACID

• Studies were carried out in healthy subjects to characterize the enterohepatic circulation of lithocholate and its metabolites [15].
• There was no statistical difference between chenodeoxycholic and ursodeoxycholic acids in their rate of biotransformation to lithocholic acid, when the total group of 14 subjects was compared [16].
• This suggests that lithocholate and ursodeoxycholate treatment leads to a rapid induction of transcytosis and that annexin II exchange occurs upon membrane fusion at all stages of the hepatocyte transcytotic pathway [17].
• We found that activation of PXR also increases the activity and gene expression of the phase II conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination [18].
• The DNA damage was repaired upon incubation of the cells in fresh medium lacking lithocholic acid [19].

Anatomical context of LITHOCHOLIC ACID

• The small lithocholate pool (about 100 mg) could be explained by rapid fecal excretion caused by sulfation which decreases passive absorption in the jejunum and active absorption in the ileum [15].
• The cholate and chenodeoxycholate derivatives produced homogeneous intracellular fluorescence and were rapidly transported to the vacuole, while the lithocholate analogue accumulated more slowly in the canalicular vacuole and gave rise to punctate fluorescence within the cell [17].
• Activation of LXRalpha in transgenic mice confers a female-specific resistance to lithocholic acid (LCA)-induced hepatotoxicity and bile duct ligation (BDL)-induced cholestasis [20].
• Marked alterations of the apical cell membrane were seen only in livers perfused with LCA and in isolated segments of the biliary epithelium [21].
• In taurine-depleted isolated livers, perfused with LCA, CDCA, or CA, bile duct epithelial cells showed no evidence of intracellular damage, despite the increased biliary excretion of unconjugated BS [21].

Associations of LITHOCHOLIC ACID with other chemical compounds

• Defective sulfation of lithocholate, the major bacterial biotransformation product of chenodeoxycholic acid, can explain accumulation of lithocholate in the enterohepatic circulation and provide a possible mechanism for the hepatotoxicity observed during chenodeoxycholic acid administration to the nonhuman primate [22].
• The squirrel monkey thus differs from humans and chimpanzees, which efficiently sulfate LCA, and is similar to the rhesus monkey and baboon in that LCA is poorly sulfated [5].
• In all 12 patients who underwent duodenal intubation before initiation of total parenteral nutrition, lithocholic acid accounted for less than 1% of total biliary bile acids [23].
• Metabolism of lethocholate in healthy man. I. Biotransformation and biliary excretion of intravenously administered lithocholate, lithocholylglycine, and their sulfates [24].
• However, after 15 min, when 99% of the radioactivity had been cleared, the disappearance curve flattened, and chromatography suggested that the chemical form of circulating radioactivity had become sulfolithocholylglycine, the end product of hepatic metabolism of lithocholate in man [25].

Gene context of LITHOCHOLIC ACID

• In particular, the secondary bile acid derivative lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a metabolic substrate for CYP3A hydroxylation [26].
• Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury [27].
• In addition, the selective induction of glucuronidation activity toward lamotrigine, ethinyl estradiol, chenodeoxycholic acid, and lithocholic acid by either PCN or TCDD in small intestine from Tg-UGT1 mice corresponded to expression of the locus in this tissue [28].
• The glucosidation by UGT2B7 was specific for HDCA and was not observed with the other bile acids examined, lithocholic acid, chenodeoxycholic acid, and ursodeoxycholic acid [29].
• A newly recognized VDR ligand is the carcinogenic bile acid, lithocholic acid (LCA) [30].

Analytical, diagnostic and therapeutic context of LITHOCHOLIC ACID

• In the 5 patients with elevated levels of biliary lithocholic acid, serum alkaline phosphatase and aminotransferase activities rose progressively at serial determinations, the increase being significant after 2 wk of total parenteral nutrition [23].
• Radioactive lithocholate was administered intravenously to female rhesus monkeys with an exteriorized enterohepatic circulation, and the chemical form of biliary radioactivity was defined by thin layer chromatography [22].
• Metabolism of lithocholate in healthy man. III. Plasma disappearance of radioactivity after intravenous injection of labeled lithocholate and its derivatives [25].
• Results of laboratory studies including liver function tests were not affected adversely and biliary lithocholic acid concentration did not increase during therapy [31].
• Contrary to our a priori hypothesis, there was no difference between the cases and either control group in their bile concentrations of lithocholate, the proportion of bile acids which were sulfated, or the concentration of nonsulfated lithocholate [32].

References