conclusion, bile acids with widely different hydrophobiBile acids have been proposed to exert immunological cities are incapable of influencing the release of IL-6 and effects of potential pathogenic or therapeutic relevance, TNFa by monocytes and Kupffer cells, provided they are yet the experimental evidence remains preliminary. We studied at noncytotoxic concentrations and in the presreexamined the effects of a variety of bile salts with difence of physiological amounts of proteins. (HEPATOLOGY fering hydrophilic-hydrophobic properties on the pro-1997;25:927-933.) duction of interleukin-6 (IL-6) and tumor necrosis factor a (TNFa) from monocytes and Kupffer cells. Monocytes from healthy human donors and Kupffer cells from 5-Infectious complications 1,2 and endotoxemia 3,4 occur freweek-old mice were incubated for up to 18 hours with quently in patients with severe cholestasis. The underlying or without varying concentrations of bile salts and lipo-mechanisms are not fully understood, yet cholestasis may be polysaccharide (LPS). Monocyte viability was ¢95% with the consequence of the impairment of cell-mediated immuup to 250 mmol/L sodium ursodeoxycholate and°90% nity 5-7 and macrophage function. 8 Endotoxins are lipopolysacwith 200 mmol/L chenodeoxycholate, decreasing sharply charides (LPS) present in the wall of gram-negative bacteria. at higher concentrations. Kupffer cells were more vul-Endotoxemia may derive from both systemic infections with nerable, particularly to chenodeoxycholate (viabilities gram-negative bacteria or from absorption of LPS from the of 25% and 0% at concentrations of 100 mmol/L and 200 gut. Normally, LPS is cleared by liver macrophages (Kupffer mmol/L, respectively). In monocytes incubated in the cells), but when their phagocytic function is impaired, as in presence of 20% fetal calf serum, neither ursodeoxycho-cholestasis, or an excessive amount of LPS is being delivered late and chenodeoxycholate, nor a variety of other un-from the intestine, endotoxins may spill over into the periphconjugated and conjugated bile acids, tested up to their eral circulation. LPS stimulates both circulating and tissue maximal noncytotoxic concentrations, influenced the macrophages to release several cytokines, 9,10 known to be po-IL-6 and TNFa production, at any level of LPS stimula-tent inflammatory mediators, 11 as well as activators of a comtion. Similar to monocytes, incubation of murine Kupffer plex immuno-metabolic cascade, 12-14 mimicking the effects of cells with ursodeoxycholate and chenodeoxycholate did acute infections. 15 This establishes a vicious cycle, aggravatnot influence cytokine release. In contrast, the addition ing the original cholestasis and often leading to multiple orof 10 nmol/L dexamethasone to monocytes significantly gan failure. On the other hand, during bacterial sepsis, the decreased TNF-a and IL-6 release (69 { 11% and 48 { liver is the main organ responsive to LPS, 16 presumably be-15%, respectively). When monocytes were incubated cause Kupffer cells are the major source...

both bile acids, biliary cholesterol is transported in nonThis 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 tauroursoHyodeoxycholic 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. [1][2][3] 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 chroma-conditions, 4 and in increased amounts in cholestatic liver distography), biliary lipid concentrations (by standard eases, 5,6 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. 7,8 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 ursodeoxyTaurohyodeoxycholic acid stimulated significantly cholic acid (UDCA) has two main clinical effects: (1) it induces greater (P õ .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, 13,14 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 refor phospholipids). The secretory ratio between phos-lated 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][21][22] and in praimmol) (P õ .05). Biliary enrichment with taurohyodeoxy-rie dogs fed a cholesterol-containing diet. [23][24][25] This effect was cholic acid was positively related with percent concen-n...

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Taurohyodeoxycholic acid is a natural 6 alpha-hydroxylated bile acid with an apparent hydrophilicity intermediate between those of tauroursodeoxycholic and taurocholic acids. We investigated in the rat the hepatobiliary metabolism, choleretic properties, and biliary maximum secretory rate (SRmax) of taurohyodeoxycholic in comparison with these two bile salts. Each compound was infused intravenously, at a rate increased in a stepwise manner from 100 to 300 nmol/min/100 g body wt, in bile salt-depleted bile fistula rats. The three bile salts appeared rapidly starting with the infusion and increased to represent more than 95% of the total bile salts. No apparent biliary metabolites were formed. All the bile salts caused a dose-dependent increase in bile flow and biliary lipid output. The absolute increase in bile flow was lower in rats infused with taurohyodeoxycholic acid, yet the volume of bile formed per nanomole of secreted bile salt was 13.8 nl for taurohyodeoxycholic, 6.4 nl for tauroursodeoxycholic acid, and 10.9 nl for taurocholic. The SRmax values were 1080, 3240, and 960 nmol/min/100 g, respectively. At all infusion rates, taurohyodeoxycholic acid caused a greater (P < 0.001) secretion of biliary lecithin compared to the other bile salts. There were no significant differences in the biliary secretion of cholesterol and proteins. Electron microscopy showed the recruitment of vesicles and lamellar bodies around and within bile canaliculi. In conclusion, taurohyodeoxycholic promotes a biliary lecithin secretion greater than expected from physicochemical predictions, representing a novel secretory property with potential pharmacological relevance.

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