both bile acids, biliary cholesterol is transported in non-This study aimed to determine the effect in humans micellar aggregates. Finally, in the conditions of our of taurohyodeoxycholic acid, a 6a-hydroxylated bile acid study, taurohyodeoxycholic acid was not hepatotoxic. with hydrophilic properties, on bile lipid secretion. Four (HEPATOLOGY 1997;25:1306-1314.) cholecystectomized patients who had gallstones and an interrupted enterohepatic circulation were intraduodenally infused with taurohyodeoxycholic and taurourso-Hyodeoxycholic acid (HDCA) is a 6a-dihydroxylated natudeoxycholic acids on separate occasions at a dose of 0.8 ral bile acid (3a-, 6a-dihydroxy-5b-cholan-24-oic acid) found to 1 g/h for 3 hours. In hourly bile samples collected for in pig and rat bile. In humans, 6a-hydroxylated bile acids 8 hours after the beginning of the infusion, biliary bile are present in trace amounts in the urine in physiological acid composition (by high-performance liquid chromaconditions, 4 and in increased amounts in cholestatic liver distography), biliary lipid concentrations (by standard eases, suggesting that in humans the 6a-hydroxylation is methods), and distribution of biliary carriers (by gel a metabolic pathway that, repressed in normal conditions, chromatography) were evaluated. Blood liver function can be derepressed in pathological situations. tests were performed before and after the infusions.
HDCA, because of the presence of a hydroxyl group in the Taurohyodeoxycholic and tauroursodeoxycholic acids 6a position of the steroid ring, is a highly hydrophilic bile became the predominant biliary bile acids in all patients acid. It is known that the enrichment of the endogenous except for one infused with taurohyodeoxycholic acid. bile acid pool with hydrophilic bile acids such as ursodeoxy-Taurohyodeoxycholic acid stimulated significantly cholic acid (UDCA) has two main clinical effects: (1) it induces greater (P รต .05) cholesterol and phospholipid secretion the dissolution of cholesterol gallstones 9,10 by a reduction of per unit of secreted bile acid (0.098 and 0.451 mmol/mmol, bile cholesterol saturation 11,12 because of a decrease in biliary respectively) compared with tauroursodeoxycholic acid cholesterol secretion, 13, and (2) it improves results of liver (0.061 mmol/mmol for cholesterol and 0.275 mmol/mmol function tests in patients with liver disease, 15-17 possibly re- for phospholipids). The secretory ratio between phoslated to a decreased detergency and cell-damaging potency pholipid and cholesterol was significantly higher after of the physiological bile acid pool. 18,19 infusion of taurohyodeoxycholic acid (3.88 mmol/mmol) HDCA has been reported to prevent gallstone formation in compared with taroursodeoxycholic acid (3.09 mmol/ hamsters fed a fat-free, glucose-enriched diet 20-22 and in prai- mmol) (P รต .05). Biliary enrichment with taurohyodeoxyrie dogs fed a cholesterol-containing diet. 23-25 This effect was cholic acid was positively related with percent concennot, however, associated with a reduction in bile cholesterol tration of phospholipids but not with that of cholesterol. saturation. In humans, attempts to enrich the bile acid pool The opposite trend was observed in tauroursodeoxywith HDCA have failed 26 ; in fact, HDCA is eliminated in a cholic acid-enriched biles. In both taurohyodeoxycholic large amount (30-84%) in the urine as a glucuronide. 27 acid-and tauroursodeoxycholic acid-rich bile, 80% to
Recently the tauroconjugate of HDCA (THDCA) has been 90% of cholesterol was carried in a gel-chromatographic synthesized. Conjugation with taurine reduces hepatic biofraction corresponding to an apparent molecular weight transformation of this bile acid, 28 increases the solubility of of 80 to 200 kd. No alteration in liver function test results the molecule, 29 and decreases its bacterial degradation in the was observed after taurohyodeoxycholic acid infusion. intestine. Accordingly, it has been shown that THDCA in-In conclusion, taurohyodeoxycholic acid stimulates fused intravenously in rats with biliary fistulas is well segreater cholesterol and phospholipid secretion than creted in the bile without biotransformation, and no altertauroursodeoxycholic acid, but with a higher phosphoations of liver function test results were observed. 31 lipid/cholesterol secretory ratio. In bile enriched with Unexpectedly, in this animal model THDCA induced a remarkable increase in biliary phospholipid secretion and concentration without parallel changes in cholesterol secretion. 31 Abbreviations: HDCA, hyodeoxycholic acid; UDCA, ursodeoxycholic acid; THCDA, tauro-Furthermore, data in vitro have shown that THDCA solubiconjugate of hyodeoxycholic acid; TUDCA, tauroursodeoxycholic acid; HPLC, high-perforlizes cholesterol gallstones faster than tauroursodeoxycholic mance liquid chromatography; CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxyacid (TUDCA). 32 cholic acid; UCA, ursocholic acid.