Biomedical subjects
Publications and source records attributed to S Erlinger.
The authors report the case of a patient with transient intrahepatic cholestasis following the administration of a soluble gold salt, sodium aurothiopropanol sulfonate. Other manifestations of intolerance to gold salts included exfoliative dermatitis and eosinophilia.
Cholestasis may result either from a disturbance of the systems responsible for solute transport into the bile canaliculi (for example, the Na+ and K+-ATP-ase system) or from an alteration of canalicular microvilli (for example, that resulting from microfilament dysfunction). Evidence that both mechanisms operate is drawn from the analysis of experimental cholestasis induced by oestrogen, cytochalasin-B, and phalloidin.
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The relationship between microsomal enzyme induction and the increase in bile flow associated with phenobarbital administration was studied in rats in three experimental situations: examination of the time-course effect of a single dose of phenobarbital (8 mg/100 g body weight) on bile flow and hepatic cytochrome P-450 concentration; study of the influence of SKF 525-A (8 mg/100 g body weight) and cobaltous chloride (6 mg/100 g body weight/day for 3 days) on the phenobarbital-induced hypercholeresis. It was observed that: (a) the maximal increase in bile flow occurred 18 h after the single injection of phenobarbital, while the maximal increase in cytochrome P-450 occurred at 48 h; (b) in rats pretreated with phenobarbital for 3 days, SKF 525-A did not suppress the hypercholeresis due to phenobarbital, and (c) in rats treated with phenobarbital and cobaltous chloride, cytochrome P-450 concentration in the liver was not increased, while bile flow was increased to approximately the same extent as in animals treated with phenobarbital alone. These results further support the hypothesis that microsomal cytochrome P-450-dependent enzyme induction and increase in bile flow are two separate effects of phenobarbital.
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The influence of phalloidin, an agent that causes irreversible polymerisation of actin into microfilaments, on bile secretion and hepatocyte ultrastructure was examined in rats. Phalloidin was given intraperitoneally at the dose of 50 microgram per 100 g of body weight per day for 1, 3, or 7 days. The following was observed. (1) Bile flow decreased, as compared to controls, by 19% after 1 day, 34% after 3 days, and 55% after 7 days. Bile acid secretion was also decreased. (2) Electron microscopic examination of the hepatocyte in treated animals revealed an increased thickness of the pericanalicular microfilamentous network and a dilatation of bile canaliculi. Stereological examination revealed an increase in the relative volume of the microfilamentous network (per unit of hepatocyte cytoplasm) of 2.55% after 1 day, 4.06% ater 3 days, and 6.16% after 7 days. (3) [14C]Erythritol biliary clearance, measured after 7 days, decreased in parallel to bile flow, suggesting that the decrease in bile flow was of canalicular origin. [14C]Sucrose biliary clearance increased in treated animals, suggesting an increased permeability of the biliary system to sucrose. There was a predominant decrease in the bile acid independent bile flow. These data provide circumstantial evidence for the hypothesis that microfilament dysfunction can produce cholestasis.
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The influence of sodium taurocholate (TC) on the hepatic uptake of phenol 3,6-dibromphthalein disulfonate (dibromosulphophthalein, DBSP) was examined in the dog. Single injections of DBSP (7.5-83.3 mg-kg-1) were given intravenously and the initial velocity of uptake (V) of the dye was calculated from the plasma disappearance rate measured during the 1st 5 min. It was observed that: a) the initial velocity of uptake of DBSP increased with the dose (D) in a nonlinear way, a finding consistent with Michaelis-Menten kinetics; the maximal initial velocity of uptake (Vmax) was 7.5+/-1.0 (SD) mg-min-1-kg body wt-1, and the half-saturation constant (Kd) was 27.7+/-7.0 (SD) mg-kg-1; b) when a TC infusion was given prior to the DBSP injection, the initial disappearance of the dye was more rapid than in the absence of the bile acid; Vmax increased to 12.3+/-2.0 (SD) mg-min-1-kg-1 (P less than 0.001) and Kd increased to 50.3+/-12.8 (SD) mg-kg-1 (P less than 0.001). These results indicate that: 1) the uptake of DBSP by the liver cell is a saturable process; 2) TC increases both the Vmax, suggesting a facilitation of the uptake process, and the Kd, suggesting competition for a common site. This effect of TC on DBSP uptake is similar to the previously described effect of this bile salt on BSP excretion into bile and suggests an interaction of bile salts with the uptake process of dyes.
The influence of four barbiturates, phenobarbital, barbital, thiopental, and pentobarbital, on bile secretion and on the hepatic microsomal system was studied in anesthetized rats. The barbiturates were injected intraperitoneally for 4 days and the animals were studied on the 5th day. It was found that: (1) phenobarbital, barbital, and thiopental, but not pentobarbital, significantly increased liver weight, cytochrome P-450 concentration in the liver, decreased pentobarbital sleeping time and induced a hypertrophy of the smooth endoplasmic reticulum in the hepatocytes at electron microscopy; (2) in contrast, the four barbiturates, including pentobarbital, significantly increased bile flow; this increase was attributed to an increase in the bile acid independent bile flow. There was no correlation between the increase in bile flow and the cytochrome P-450 concentration in the liver. It is concluded that the increase in bile flow observed after barbiturate treatment in the rat is possibly independent of the hepatic microsomal enzyme induction produced by these drugs.
A retrospective study was carried out to examine the influence of portacaval shunt (PCS) on serum bile acid concentration in 47 cirrhotic patients. Cirrhotic patients with PCS had a significantly higher serum bile acid concentration than cirrhotic patients without PCS whatever the duration between the diagnosis and the time of measurement. Serum bile acid concentration was significantly higher 3--12 months after PCS (67.90 +/- SD 15.90 micrometer; p less than 0.001) and 12 months or more after PCS (94.11 +/- SD 33.86 micrometer; p less than 0.001) than before the shunt (18.98 +/- SD 13.62 micrometer). The mean concentration 12 months or more after PCS was significantly higher than that found 3--12 months after shunt (p less than 0.02). This progressive increase in serum bile acid concentration may indicate a deterioration of hepatic function in shunted patients.
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The purpose of this work was to validate for taurocholate and taurochenodeoxycholate the multiple infusion method of Wheeler et al. previously used for the study of hepatic sulphobromophthalein transport and to obtain numerical estimates of the relative storage capacity and secretory transport maximum of both bile acids. Experiments were performed in anaesthetized dogs after depletion of the endogenous bile acid pool. Bile was collected continuously to prevent recirculation of bile acids and to measure their secretion rates. Taurocholate or taurochenodeoxycholate were infused intravenously at 3 different rates and blood samples were collected every ten min to measure serum bile acid concentrations. Extrahepatic distribution spaces of taurocholate and taurochenodeoxycholate were measured by an isotope dilution method. Serum bile acid concentrations varied linearly with time during the last 30 min of each infusion period. A linear relationship was found between the calculated hepatic removal rate and the rate of change of serum bile acid concentration. The mean values of relative storage capacity were (in mumol.mumol-1.l-1.kg body weight-1) 0.16 +/- SD 0.07 for taurocholate and 0.08 +/- SD 0.03 for taurochenodeoxycholate. The mean values for secretory transport maximum were (in mumol.min-1.kg body weight-1) 4.81 +/- SD 1.24 for taurocholate and 3.56 +/- SD 0.60 for taurochenodeoxycholate. The values of secretory transport maximum with the multiple infusion method were only slightly higher than those obtained by direct measurement of biliary secretion. The values of relative storage capacity obtained during infusions resulting in decreasing plasma concentrations were usually lower than those obtained when the plasma concentration increased. This suggests that the limitations of the method previously noted for sulphobromophthalein may apply to bile acids.
131I-labeled BSP is obtained by the incorporation of one molecule of radioactive iodine in BSP. The purpose of this work was to study the influence of the added iodine on the hepatic extraction and biliary excretion of BSP. Two types of experiments were performed. In the first, a compartmental analysis of BSP and 131I-labeled BSP disappearance curves was performed after the simultaneous injection of 5 mg per kg of b. wt. of BSP and 10 muCi of 131I-labeled BSP: both, the plasma to liver and liver to bile transfer rates were significantly lower for 131I-labeled BSP than for BSP; the liver to plasma transfer rates were not significantly different. In the second series of experiments, the hepatic uptake of BSP and 131I-labeled BSP was estimated by the multiple indicator dilution technique: the extraction of BSP (59% +/- SD 5) was significantly higher than that of 131I-labeled BSP (35% +/- SD 5) (P less than 0.001). In conclusion the labeling of BSP with 131I significantly modified the hepatic handling of the dye; 131I-labeled BSP cannot therefore be used as a tracer of BSP.
The relationship between taurocholate or taurochenodeoxycholate secretion and cholesterol and phospholipid secretion in bile was studied in anaesthetized dogs infused with graded doses of these bile acids. Cholesterol output was linearly related to bile acid output during both taurocholate and taurochenodeoxycholate infusions. On the average 1.45 nmol and 4.70 nmol of cholesterol were secreted per mumol of taurocholate or taurochenodeoxycholate respectively (P less than 0.001). A linear relationship was also observed between phospholipid secretion rate and taurocholate or taurochenodeoxycholate secretion rates. However, the amounts of phospholipid secreted per mumol of taurocholate or taurochenodeoxycholate (respectively 0.10 and 0.15 mumol) were not significantly different. Thus, bile was less saturated with cholesterol during taurocholate infusions than during taurochenodeoxycholate infusions. These results are consistent with the hypothesis that micelle formation by bile acids is a major determinant of cholesterol and phospholipid secretion in the dog.
The effect on sulfobromophathalein transport maximum (Tm) and biliary lipid secretion of sodium glyco-24,25-dihydrofusicate, a micelle-forming compound secreted into bile, has been studied in the hamster and compared to that of a physiological bile salt, sodium taurocholate. Biliary phospholipid and cholesterol secretion increased both during glycodihydrofusidate and taurocholate administration, an observation which suggest that both compounds increased th biliary secretion of micelle-forming compounds. In contrast, only taurocholate increased sulfobromophthalein Tm into bile, while glycodihydrofusidate administration decreased it. This observation suggests that the increase in sulfobromophthalein Tm observed during taurocholate administration is not the result of micellar sequestration. It could rather be the consequence of a specific effect of bile salts on the dye transport system.
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