Gastroesophageal reflux (GER) and microaspiration of duodenogastric refluxate have been recognized as a risk factor for pulmonary fibrosis. Recent evidence suggests that bile acid microaspiration may contribute to the development of lung fibrosis. However, the molecular evidence is scarce and the underlying mechanisms remain to be elucidated. We have recently demonstrated that bile acids induce activation of alveolar epithelial cells (AECs) and lung fibroblasts in vitro . In the present study, a rat model of bile acid microaspiration was established by weekly intratracheal instillation of three major bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and lithocholic acid (LCA). Repeated microaspiration of CDCA, DCA, and LCA caused fibrotic changes, including alveolar wall thickening and extensive collagen deposition, in rat lungs. Bile acid microaspiration also induced alveolar epithelial–mesenchymal transition (EMT), as indicated by up-regulation of mesenchymal markers α-smooth muscle actin (α-SMA) and vimentin, as well as down-regulaton of epithelial markers E-cadherin and cytokeratin in alveolar epithelium of rat lungs. The expression of fibrogenic mediators, including transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and periostin, was significantly elevated in rat lungs exposed to microaspiration of bile acids. Furthermore, microaspiration of bile acids also induced p-Smad3 and farnesoid X receptor (FXR) expression in rat lungs. Our findings suggest that microaspiration of bile acids could promote the development of pulmonary fibrosis in vivo , possibly via stimulating fibrogenic mediator expression and activating TGF-β1/Smad3 signaling and FXR.

1. Administration of α-naphthylisothiocyanate (ANIT) to rats produced dose-dependent increases in plasma bile acid and bilirubin concentrations. Similar increases in plasma bile acid and bilirubin concentrations were evident in bile duct ligated rats, indicating that the severity of cholestasis is almost identical in both models. 2. Plasma alkaline phosphodiesterase I was increased by only 50–80% while alkaline phosphatase was increased more than threefold after ANIT administration. This is in contrast to an earlier study [S. R. Simpson, K. Rahman & D. Billington (1984) Clinical Science 67, 647–652] where, after bile duct ligation, serum alkaline phosphodiesterase I was elevated sixfold before any increase in alkaline phosphatase activity became apparent. Thus, plasma alkaline phosphodiesterase I does not offer as sensitive a marker of intrahepatic cholestasis (induced by ANIT) as it does of extrahepatic cholestasis (induced by bile duct ligation). 3. Hepatic alkaline phosphodiesterase I was unaffected by ANIT pretreatment while hepatic alkaline phosphatase was increased up to seven times. It is suggested that raised plasma alkaline phosphodiesterase I is due to regurgitation of the biliary enzyme rather than overspill of the enzyme from liver into blood. 4. Gel filtration showed that 24 h and 96 h after ANIT administration, rat serum contained a high molecular weight form of alkaline phosphodiesterase I, suggesting a different isoenzyme profile.

1. Isolated rat livers were perfused in a single pass with increasing doses of taurocholate with and without albumin in the perfusion media. 2. The kinetics of taurocholate uptake were thus evaluated. 3. In all the experiments, taurocholate uptake showed Michaelis-Menten kinetics. Increasing the albumin concentration in the medium resulted in an increase in the K m , without effect on the V max . When taurocholate and albumin were kept constant (20:1 molar ratio), the V max was significantly lower than in the other experiments. 4. These data suggest that taurocholate uptake shows saturation in the absence of albumin and that albumin reduces taurocholate uptake.

1. Biliary lipid secretion rates were measured in non-obese and obese individuals with and without cholesterol gallstones, using a steady-state, amino acid duodenal perfusion method. In addition, biliary lipid secretion rates were measured in five obese gallstone patients receiving high-dose chenodeoxycholic acid therapy (16-22 mg day −1 kg −1 ). 2. Bile acid secretion rates in the non-obese patients with cholesterol gallstones (563+sem 70 μmol/h, n = 6) were significantly lower than in the non-obese controls (1078 + 210 μmol/h, n = 10, P < 0.05), whereas cholesterol secretion rates were similar in the non-obese individuals with and without gallstones (51+7 and 42+4 μmol/h respectively). 3. In the obese, both with and without gallstones, the major abnormality was hypersecretion of cholesterol (107+7 μmol/h, n = 7, and 81 + 15 μmol/h, n = 7, respectively). Both these values were significantly greater than those in the non-obese controls ( P < 0.01-0.02). 4. Biliary cholesterol secretion rates correlated significantly with bile acid secretion rates but, for every mole of bile acid secreted, the obese secreted more cholesterol than the non-obese. 5. Chenodeoxycholic acid treatment lowered biliary cholesterol saturation in obese gallstone patients by reducing biliary cholesterol secretion. 6. These results suggest that there are two major types of defect in biliary lipid secretion in gallstone patients: reduced biliary bile acid secretion in non-obese gallstone patients and excessive biliary cholesterol secretion in the obese.

1. The renal clearances of [ 14 C]glycocholate, [ 14 C]taurocholate and [ 3 H]glycochenodeoxycholate-3-sulphate were determined in bile duct obstructed rats. 2. Comparisons of the bile acid clearances with glomerular filtration rates (GFR) indicate that most of the filtered bile acids are reabsorbed. 3. Inhibition studies with p -aminohippurate (PAH) and probenecid suggest that a proportion of the bile acids in urine is secreted. 4. Attempts were made to increase the renal clearance of the bile acids by the administration of pharmacological agents. 5. An infusion of sodium acetate (0.3 mol/l) increased the clearance of the radioactive bile acids and augmented the urinary excretion of endogenous 3α-hydroxy bile acids and reduced their concentration in plasma.

1. The biliary excretion of total bilirubin and bile acids, and the fate of tracer doses of radioactive sulphated and non-sulphated bile acids, were studied in patients with percutaneous transhepatic bile drainage. 2. Non-sulphated bile acids were excreted in bile early after biliary decompression, and the serum total 3α-hydroxy bile acid concentrations fell rapidly to normal. Biliary bilirubin excretion was both less than and delayed compared with that of bile acids, and the serum bilirubin concentration fell more slowly. 3. The serum disappearance of [ 3 H]chenodeoxycholate-3-sulphate was slower than that of [ 14 C]glycocholate in all patients with bile drainage, the difference being more marked in the jaundiced patients. 4. The radioactive sulphated bile acids were recovered predominantly in the urine of the jaundiced patients. In contrast [ 14 C]glycocholate was excreted almost exclusively in bile. In an anicteric patient, radioactive sulphated bile acid disappeared from the serum more quickly, and biliary recovery exceeded that in the urine. 5. The studies demonstrate the differences in handling of total bilirubin, and sulphated and non-sulphated bile acids in man after the relief of bile duct obstruction. The biliary excretion of radioactive labelled sulphated bile acids is low for at least 1 week after biliary drainage, but later becomes the predominant route for excretion in the anicteric patient.

1. Sera from patients with fulminant hepatic failure (FHF) has previously been shown to contain substance(s) which inhibit leucocyte ouabain-sensitive sodium efflux and rat brain Na + ,K + -dependent ATPase in vitro. Similar effects in the patients could be an important mechanism in the development of encephalopathy and cerebral oedema. 2. In previous studies, bilirubin, free fatty acids and mercaptans have been shown to inhibit Na + ,K + -ATPase in vitro. The present report is concerned with the effects of a number of other potentially toxic substances present in the serum of patients with FHF. 3. Chenodeoxycholic acid, p -hydroxyphenyllactic acid, p -hydroxyphenylpyruvic acid and endotoxin caused 30–45% inhibition of partially purified rat brain Na + ,K + -ATPase at concentrations known to occur in the serum of patients with FHF. At low concentrations the inhibitory effects of these substances were additive, but at higher concentrations a maximum level of inhibition was reached. 4. These further substances are likely, therefore, to be of importance in the disturbances of brain function found in FHF.

1. The biliary maximum secretory rate (SR max. ) of glycoursodeoxycholate in the bile fistula anaesthetized rat was about five times that of unconjugated ursodeoxycholate. 2. Likewise, the biliary SR max. of tauro-7-ketolithocholate was more than three times that of unconjugated 7-ketolithocholate. The SR max. of 7-ketolithocholate infused with taurine (to avoid depletion of the taurine pool) was still significantly lower than that of exogenous tauro-7-ketolithocholate. 3. These data support the hypothesis that, for bile acids that are poorly water soluble, the maximal biliary secretion rate is dependent on conjugating capacity, which is the limiting step in the overall transport from plasma into bile.

1. The hepatic extraction ratios of chenodeoxycholic acid and ursodeoxycholic acid have been measured in 12 patients without, and 20 patients with, liver disease. 2. Ten of the patients without liver disease were studied during cardiac catheterization, with a continuous infusion technique. Two of the patients without liver disease and all those with liver disease received an intravenous bolus of [ 14 C]chenodeoxycholic acid or [ 14 C]ursodeoxycholic acid, during transvenous liver biopsy. 3. The extraction ratio of chenodeoxycholic acid was 0·63 ± 0·03 (mean ± sem ) and of ursodeoxycholic acid 0·53 ± 0·01, in the patients without liver disease. In those with mild liver disease, extraction was slightly impaired (chenodeoxycholic acid: 0·49 ± 0·03; ursodeoxycholic acid: 0·43 ± 0·05), whereas in those with more severe liver disease it was greatly reduced (chenodeoxycholic acid: 0·16 ± 0·08; ursodeoxycholic acid: 0·07 ± 0·01). 4. The results suggest that (a) direct measurements confirm the accuracy of indirect estimates of hepatic extraction of chenodeoxycholic acid, (b) hepatic extraction of chenodeoxycholic acid is lower than that of cholic acid and glycocholic acid, but higher than that of ursodeoxycholic acid, (c) progressive impairment of the extraction ratios of these two bile acids occurs as the severity of liver disease increases, and (d) the ratios are correlated with indocyanine green extraction ratios.

1. Pruritus was assessed in 19 patients by measurement of nocturnal limb movement. 2. Serum (nine pruritic, ten non-pruritic) and interstitial fluid (five pruritic, three non-pruritic) bile acids were fractionated according to their mode of conjugation by using DEAP-Sephadex LH-20 and measured by gas chromatography—mass spectrometry. 3. No correlation was found between serum or interstitial fluid total bile acid or individual bile acid concentrations and pruritus. Bile acid profiles in the two groups of patients were similar and there was no correlation between pruritus and the conjugation pattern. 4. The bile acid profile of interstitial fluid reflected that of serum and a linear relationship was found between serum and interstitial fluid bile acid concentrations ( r = 0·95, P < 0·001). 5. The proportion of bile acid sulphate in interstitial fluid was significantly smaller than that in serum ( P < 0·025), where sulphates accounted for up to 46% of the total bile acids. 6. In three patients, a decrease in serum bile acid concentrations achieved by percutaneous transhepatic biliary drainage had little or no effect on pruritus. 7. These findings suggest that bile acids do not have a causative role in the pruritus of cholestatic liver disease.

1. Serum bile acids in seven patients with adult type myotonic dystrophy and 22 normal persons were quantitatively analysed by gas—liquid chromatography and gas chromatography—mass spectrometry for cholesterol, γ-glutamyltransferase and bilirubin. There was no bile obstruction in any patient. 2. Deoxycholic acid values in all mothers of patients with congenital type myotonic dystrophy were three times (2.1 μmol/l) that of the control (0.7 μmol/l). 3. Uncommon bile acids were detected in the patients' sera. One of them appeared to be dihydroxymono-oxocholanic acid, having a longer side chain. Another one appeared to be dihydroxycholanic acid, with a steroid-nucleus structure similar to chenodeoxycholic acid and with a longer side chain. 4. Biliary bile acids from three patients and one normal person were also analysed, and this revealed a remarkable decrease in ursodeoxycholic acid in the patients. 5. The presence of bile acid abnormality in patients with myotonic muscular dystrophy is proposed.

1. Obstructive jaundice sensitizes the kidney to anoxic damage. To clarify further this phenomenon the effect of unilateral infusion of bile on kidney function was studied. The contralateral intact kidney served as control. 2. Intrarenal infusion of diluted bile (1:10) resulted in an ipsilateral fourfold increase in mean rate of urinary flow ( P < 0.01), threefold increase in mean fractional excretion of sodium ( P < 0.05) and more than 50% increase in mean rates of potassium excretion ( P < 0.05). Urinary flow rate and electrolyte excretion returned to baseline upon cessation of bile infusion. The mean clearances of inulin and p -aminohippurate were unchanged during intrarenal bile infusion. 3. Intrarenal infusion of isotonic taurocholate solution (20 mmol/l) mimicked the diuretic, natriuretic and kaliuretic effects of diluted bile, whereas intrarenal infusion of bilirubin did not cause any change in the excretion of electrolytes. 4. It is concluded that increase in circulating bile acids rather than hyperbilirubinaemia may alter kidney function during obstructive jaundice. Acute cholaemia may cause volume depletion by increasing urinary salt loss. This in turn may aggravate the direct nephrotoxicity of circulating bile compounds.

1. the apparent renal clearance of intravenously injected [ 14 C]glycocholate and [ 3 H]-chenodeoxycholate-3-sulphate was estimated in 22 patients with cholestasis. the degree of protein binding of the isotopes in serum from these patients was determined. the effects of pharmacological agents, changes in urine flow rate and pH on renal clearance were studied. 2. the mean renal clearance of [ 14 C]glycocholate was 1.7 ± 0.4 ml/min (mean ± sem), and that of [ 3 H]chenodeoxycholate-3-sulphate was 6.4 ± 0.9 ml/min. [ 14 C]Glycocholate was 80.1% protein bound and [ 3 H]chenodeoxycholate-3-sulphate 96.5% protein bound. 3. Comparisons of the observed clearance rates with those calculated on the basis of glomerular filtration of the unbound fraction suggest that whereas [ 14 C]glycocholate is predominantly reabsorbed by the renal tubules, [ 3 H]chenodeoxycholate-3-sulphate appears in the urine mainly as the result of tubular secretion. 4. Probenecid, ethacrynic acid, frusemide and bendrofluazide decreased the clearance of both bile acids, implying competition for secretion via the proximal tubular organic acid secretory pathway between these compounds and bile acids. 5. Passive non-ionic diffusion does not seem to be an important mechanism in the renal excretion of bile acids as changes in urine flow rate and pH did not influence bile acid clearance. 6. A greater affinity of the proximal tubular organic acid secretory pathway for sulphated than for non-sulphated bile acids may explain the higher observed renal clearance rate of sulphated bile acids.

1. The fasting plasma disappearance curve of [ 14 C]glycocholic acid after intravenous injection was compared in nine normal subjects with that obtained 100 min after a standard liquid test meal. 2. Plasma disappearance curves of indocyanine green were determined in 13 normal subjects under the same conditions. 3. Plasma clearances were significantly increased after the meal for both [ 14 C]glycocholic acid (median 455 ml min −1 m −2 , range 376–672 increased to 704, 528–1968; P < 0.01) and indocyanine green (359, 227–473 increased to 435, 358–985; P < 0.01). 4. Median initial volume of distribution was unaltered, but in four subjects it was greatly increased after the meal, although no alteration in plasma volume, measured with Evans blue dye, was observed. 5. The increased postprandial plasma clearance of glycocholic acid is probably due to an increase in liver blood flow, and suggests that in health this part of the enterohepatic circulation of bile acids also varies with meals.

1. The hepatic extraction ratio of 14 C-labelled bile acids has been measured directly by hepatic vein catheterization in five patients without liver disease (glycocholic acid, three; cholic acid, two) and in 16 patients with histologically confirmed liver disease (glycocholic acid, seven; cholic acid, nine). 2. After intravenous administration of [ 14 C]-glycocholic acid by bolus injection (two control subjects) or constant infusion (one control subject), directly measured hepatic extraction ratio was 0.91, 0.84 and 0.88, greater than that for indocyanine green. The extraction ratio of [ 14 C]cholic acid in two subjects was 0.72 and 0.70, confirming a lower extraction of the unconjugated bile acid. 3. The hepatic extraction ratio of both bile acids was reduced in patients with chronic liver disease (range 0.07–0.69), although the extraction ratio of glycocholic acid remained normal in one patient with viral hepatitis. 4. Estimates of liver flow calculated from the extraction of [ 14 C]glycocholic acid, but not cholic acid, correlated with those calculated from indocyanine green kinetics, although numbers were small. 5. Measurement of the hepatic extraction of individual bile acids, not previously reported in man, allows a more accurate description of the enterohepatic circulation.

1. Self-filling blind loops of jejunum were constructed in three groups of rats; in the first, blind loops were created without further manipulation; in the second the bile was diverted permanently into the lower ileum below the blind loop, whereas in a third neomycin was added to the drinking water throughout the experiment. Two weeks after the creation of the blind loops, they were used for structural and functional studies. 2. Morphometric and microdissection techniques demonstrated that the surface area of the individual villi of the mucosa of ‘ordinary’ blind loops had increased fourfold in comparison with corresponding control jejunum, whereas the increase was only twofold in rats with bile diversion or in the series treated with neomycin. There were proportional increases in crypt length and mitotic activity of the crypts in all three series, which suggest that the alterations in the mucosa were due to hyperplasia in both villus and crypt compartments. 3. Sucrase, succinate dehydrogenase, alkaline phosphatase and non-specific esterase activities, determined biochemically or histochemically, were reduced in the mucosae of all blind loops, though the changes were most pronounced in the ‘ordinary’ blind loops. The accumulation of l-phenylalanine by mucosal slices in vitro was depressed, although the decrease was less marked in the series treated with neomycin. 4. These results suggest that both bacteria and deconjugated bile acids play a role in the development of the hyperplastic changes of the blind-loop mucosa, but that another factor might also be involved: as a possible candidate, stasis of the intestinal contents was considered. 5. To test this hypothesis, loops of rat colon were transposed into the jejunum. Above the transposed loop, the jejunal mucosa developed hyperplasia of both villus and crypt compartments, with a reduction in its ability to accumulate l-phenylalanine. It is argued that these changes, probably caused by stasis of the intestinal contents, are triggered off by the dilatation of the gut, which may also be implicated in the mucosal alterations in blind loops.

1. Rats were subjected to resection of either the distal 50 cm of small bowel, the caecum or a combined ileocaecal operation. The effects on stool production and growth were observed over the following 8 weeks. Subsequently measurements were made at various levels in the remaining gut of intestinal weight, mucosal thickness, mucosal adenosine 3′:5′-phosphate (cyclic AMP) concentration and the water and bile acid content of luminal material. 2. Rapid adaptation, in terms of growth and the production of formed stools, was seen after ile-ectomy or caecectomy. This was slower and less complete after ileocaecectomy. Changes in water content indicated that colonic absorption of water was normal after ile-ectomy but impaired after ileocaecectomy. 3. After ile-ectomy there was growth of the caecum but not colon, whereas after ileocaecectomy there was growth of the remaining colon. 4. The intraluminal bile acid concentration in the small-gut remnant was markedly decreased at 2 weeks with little further change at 8 weeks after ileal resection. The colonic intraluminal bile acid concentration was only modestly increased after ile-ectomy or ileocaecectomy. 5. When studied by a perfusion technique in vivo , deoxycholate (2·5 mmol/l) in intact rats induced a net secretion of water into the colon; by contrast the colon of 8 week ile-ectomized rats absorbed water, although this was at a reduced rate compared with control rats. Deoxycholate increased mucosal cyclic AMP concentrations in the intact rats but not in the ile-ectomized rats. 6. Sodium ricinoleate (5·0 mmol/l) inhibited colonic water absorption and when mixed with deoxycholate (2·5 mmol/l) the effect on water transport was summatory. However, ricinoleate either alone or with deoxycholate did not alter mucosal cyclic AMP concentrations. 7. These results demonstrate that the colon can absorb water effectively after ile-ectomy in spite of being exposed to increased concentrations of luminal bile acids. This may result in part from an altered mucosal response to secretagogues. If so this represents a form of functional adaptation by the colon to ileal resection.

1. The bile acids and bile acid sulphates in the urine, serum and bile of eight cholestatic patients were studied quantitatively by gas-liquid chromatography and gas-liquid chromatography/mass spectrometry. 2. The primary bile acids (cholic acid and chenodeoxycholic acid) comprised on average 94% of the total bile acids in bile, 70% in the serum and 64% in urine. 3. The percentage composition of bile acids in bile was relatively constant and was not influenced by the degree of cholestasis. In contrast, in the serum only the primary bile acids were increased, the concentrations of the secondary bile acids (deoxycholic acid and lithocholic acid) and the minor bile acids remaining constant. 4. The data do not support the hypothesis that monohydroxy bile acids accumulate in cholestasis and are related to the pathogenesis of this syndrome. 5. The pattern of bile acid urinary excretion was similar to that in the serum. But in one patient, 3α,7β,12α-trihydroxy-5β-cholan-24-oic acid was a principal urinary bile acid, although very low concentrations of the compound were found in that patient's serum, suggesting that some of the minor bile acids in urine may originate by epimerization in the kidney. 6. In bile only a small proportion of the bile acids was sulphated (range 2·1–4·6%) and in serum the degree of sulphation was very variable (9–50%). However, in urine, sulphate esters accounted for a large proportion of the total bile acids (33–72%). 7. The output of bile acid sulphate in the urine was related to the urine total bile acid output but the serum concentration of bile acid sulphate remained relatively constant. Consequently, in contrast to the non-sulphated bile acids, whose renal clearance was relatively constant, the renal clearance of sulphated bile acids was directly related to the urine total bile acid output. This finding is inconsistent with the earlier hypothesis that their predominance in urine was due to a high renal clearance. It may indicate renal synthesis of some of the bile acid sulphates in the urine and/or inhibition of active renal tubular reabsorption of sulphated bile acids by non-sulphated bile acids.

1. The uptake of bilirubin was studied in the perfused rat liver by a multiple-indicator dilution technique employing the three-compartment model of Goresky. 2. The kinetics of hepatic bilirubin uptake could be described by the Michaelis—Menten equation. 3. The maximal uptake velocity ( V max .) and the apparent half-saturation constant ( K m ) were 4·4 ± 0·5 nmol s −1 g −1 of liver and 58 ±16 nmol/g of liver respectively, indicating that the hepatic uptake system for bilirubin under normal conditions is operating far below saturation. 4. Sodium taurocholate did not compete with bilirubin for hepatic uptake. 5. These findings are consistent with the concept that carrier-mediated transport is responsible for hepatocellular uptake of bilirubin and that bilirubin and bile acids enter the hepatocyte via separate pathways.

1. Perfusion of the human jejunum with low concentrations of glycine-conjugated bile acids in physiological solutions induced net fluid flow that varied between absorption and secretion, with only slight variation of the luminal osmotic and ionic milieu. 2. Transmucosal net flux rates for water and the principal ions were calculated. Regression analysis of the flux data was consistent with the concept of a ‘net transported fluid’ which was iso-osmotic with respect to the lumen, with a superimposed fixed net anion exchange unaffected by the rate or direction of bulk flow. 3. Recalculation of earlier data from comparable studies of the human colon showed similar relationships consistent with varying iso-osmotic bulk flow and fixed ion exchange, the latter differing from that found in the proximal bowel. 4. Studies were performed also in the human ileum. Variable iso-osmotic bulk flow was again encountered, but ion exchange was of a lower magnitude than in the jejunum or colon. Qualitatively, ion exchange in the ileum was intermediate between the jejunum and colon. 5. These analyses suggest that transmucosal bulk flow and ion exchange may be quantitatively and spatially independent processes. They provide support for the hypothesis that bulk flow may be intercellular (and hence extracellular), while ion exchange may take place across the luminal face of the mucosal cell. 6. Secretory agents, such as the dihydroxy bile acids, provide a useful means of analysing solute-solvent flow relationships in greatly differing bulk flow conditions with relatively stable physicochemical parameters.

1. The effect of conjugated and unconjugated bile acids in various concentrations on the absorption of water, sodium and chloride in the proximal jejunum in man has been studied using a perfusion system incorporating a proximal occluding balloon. 2. Unconjugated cholic acid and its glycine and taurine conjugates had no significant effect on water and electrolyte absorption. Unconjugated deoxycholic acid significantly inhibited water and electrolyte absorption at 3 m m concentration and net secretion occurred at concentrations of 5 m m , 7 m m and 10 m m . Similar results were found when taurodeoxycholic and glycodeoxycholic acid solutions were used. A greater effect was noted when higher concentrations of bile acids were used. 3. Unconjugated chenodeoxycholic acid caused net water and electrolyte secretion at 3 m m concentration and this effect became more marked with higher bile acid concentrations. Inhibition of absorption also occurred with taurochenodeoxycholic acid in a concentration of 3 m m and net secretion occurred at a concentration of 10 m m . 4. The results show that dihydroxy bile acids, conjugated or unconjugated, inhibit water and electrolyte absorption in the proximal jejunum in low concentration and cause net secretion in high concentration.

1. [ 14 C]Cholesterol was administered intravenously via the umbilical vein to foetal sheep in the latter half of gestation, and the incorporation of radioactive label into foetal bile acids was assessed. 2. After 4 days, 0·5–2% of the radioactive label was found in foetal bile. Seventy to eighty per cent of the radioactive label in foetal bile was present as [ 14 C]taurocholic acid and [ 14 C]taurochenodeoxycholic acid. The remainder was [ 14 C]cholesterol. No radioactive label was found in taurodeoxycholic acid, or in any of the glycine-conjugated bile acids. 3. It is concluded that the foetal sheep liver in the second half of gestation synthesizes taurocholic acid and taurochenodeoxycholic acid. However, the secondary bile acid taurodeoxycholic acid and the glycine-conjugated bile acids, present in foetal bile, have been acquired by placental transfer from the mother.

1. Clearance of [ 14 C]cholic acid from the systemic circulation was studied in six normal subjects and eight patients with biopsy-proven hepatic cirrhosis. In both groups, during fasting, the curve for disappearance of radioactivity from the serum during the first 100 min after [ 14 C]cholic acid injection was double-exponential in form. During the early phase, clearance was significantly more rapid, and concentrations of conjugated and free bile acid were significantly lower, in normals than in cirrhotics. 2. Radioactivity disappeared from the systemic circulation of normals within 3 h, and neither intravenous cholecystokinin nor the ingestion of food influenced serum radioactivity. Almost all cirrhotic patients had ‘spontaneous’ rises in serum radioactivity, which began approximately 2 h after [ 14 C]cholic acid injection. Cholecystokinin or food given 4–8 h after [ 14 C]cholic acid administration, produced rises. Continuous aspiration of duodenal juice markedly reduced these rises. Reinfusion of duodenal juice into the upper intestine was followed by a rise in serum radioactivity. 3. All rises were due, almost exclusively, to conjugated bile acids. 4. Impaired bile acid clearance in cirrhotics may result from inefficient hepatic extraction of bile acids, increased leakage of conjugated bile acids from hepatic cells and shunting from portal to systemic circulations. The latter factor is probably responsible for elevated, fluctuating, plasma bile acid concentrations in cirrhotic patients.

1. The effects of phenobarbitone on cholesterol and bile acid metabolism have been examined in healthy humans. 2. In three of four subjects the faecal excretion of bile acids was increased by phenobarbitone. This was associated with an increased pool size and turnover of cholic acid. Cholesterol excretion was not clearly affected. The fourth subject who did not respond was also exceptional in not showing an increase in the plasma clearance of antipyrine. 3. The three responsive subjects also developed significant increases in plasma cholesterol and triglyceride concentrations. These findings were associated with an early rise in very-low-density lipoprotein and a fall in plasma cholesterol specific radioactivity in one patient, changes compatible with increased cholesterol synthesis.

1. A 7α-hydroxysteroid dehydrogenase preparation isolated from a strain of Escherichia coli provides a specific and rapid means for the determination of 7α-hydroxy bile acids and their conjugates. 2. When used in conjunction with 3α-hydroxysteroid dehydrogenase the method enables the concentrations of primary and secondary bile acids and salts in biological fluids to be determined directly without the use of thin-layer chromatography. 3. When used with thin-layer chromatography the method allows the specific quantitative determination of chenodeoxycholic acid or its conjugates in the presence of deoxycholic acid and its derivatives.