Changes in the expression of genes related to bile acid synthesis and transport by the rat liver during hepatocarcinogenesis

The relationship between BA (bile acid) secretion (measured by GC–MS) and the expression of genes (measured by reverse transcription real-time PCR) involved in liver BA transport and metabolism was investigated at 20 and 32 weeks during rat hepatocarcinogenesis. A progressive loss of mRNA for transporters (more marked for Ntcp, Bsep and Mrp2 than for Oatp1/Oatp1a1, Oatp2/Oatp1a4 and Oatp4/Oatp1b2) was found. The mRNA levels of Cyp7a1 and the nuclear receptors FXR (farnesoid X receptor), SHP (small heterodimer partner) and FTF (α-fetoprotein transcription factor) were not modified, whereas those of Cyp8b1 were enhanced and those of Cyp27 were reduced. Biliary secretion of CA (cholic acid) remained unchanged, whereas that of CDCA (chenodeoxycholic acid) and other non-C12-hydroxylated BAs was diminished. The re-appearance of ‘flat-BAs’ (mainly allo-BAs at 20 weeks and Δ4-unsaturated-BAs at 32 weeks) probably reflects the progressive decrease observed in the expression of 3-oxo-Δ4-steroid 5β-reductase, together with the maintenance of steroid 5α-reductase type I. A significant correlation between the 5α-reductase/5β-reductase ratio and bile output of ‘flat-BAs’ was found. In conclusion, during rat hepatocarcinogenesis, the expression of transporters/enzymes responsible for BA homoeostasis is changed due to mechanisms other than those controlled by FXR/SHP/FTF. These modifications result in the re-appearance of ‘flat-BAs’, together with an increased CA/CDCA ratio in bile.

The effect of cyclosporine A on bile secretion in dogs

Cyclosporine A is reported to cause cholestasis, but the evidence is confounded by anesthesia and surgery used in acute experiments. To better investigate the effect of cyclosporine on the liver, bile output was directly measured in three cholecystectomized dogs by cannulating the common duct through a chronic duodenal fistula. Control studies were done 1 month after surgery. Cyclosporine in oral doses of 5, 15, and 50 mg∙kg−1∙d−1 was then given for consecutive 1-week periods. Twice during each study period, bile output was measured for 5 h in fasted, awake animals: 3 h to establish basal conditions, followed by 2 h of taurocholate infusions at 1 and then 2 μmol∙kg−1∙min−1. Under basal conditions, bile flow rose with each dose of cyclosporine, increasing 63, 127, and 179% above control with cyclosporine 5, 15, and 50 mg∙kg−1∙d−1 respectively. Bile flow increased similarly during taurocholic acid stimulation. Cyclosporine had no effect on bile salt or bilirubin secretion. In this chronic dog model isolated from other causes of cholestasis, cyclosporine did not induce cholestasis but rather caused a dose-related choleresis without any change in bile salt secretion.Key words: cyclosporine A, bile, cholestasis, hepatotoxicity.

Effect of pancreatic polypeptide on gallbladder pressure and hepatic bile secretion

Intraluminal gallbladder pressure, measured by radiotelemetry, and bile output were monitored during infusion of porcine pancreatic polypeptide (PP) at doses of 6, 25, 100, and 400 pmol . kg-1 . h-1 in healthy conscious pigs. Plasma PP concentrations during infusion of the three lower doses, measured by radioimmunoassay, were within the range seen postprandially in these animals. Gallbladder pressure fell in a dose-related manner during PP infusion by 2.2 +/- 0.9, 8.2 +/- 0.4, 11.6 +/- 0.7, and 14.8 +/- 0.8 mmHg, respectively. In addition, a significant reduction in the bile output was observed during infusion of the two higher doses of PP. In a separate series of experiments, using cholecystectomized pigs, PP had no effect on bile output. These findings suggest that the amount of PP released postprandially may be sufficient to influence gallbladder function but not hepatic secretion of bile in the pig.

ÜBER GALLENFLUSS UND GALLENZUSAMMENSETZUNG BEI EPINEPHREKTOMIERTEN RATTEN

ABSTRACT Bile was collected by choledochus cannulation in normal and in adrenalectomized rats. The electrolyte balance was maintained by intake of physiological saline. In the adrenalectomized animals the bile potassium level was increased and the sodium level decreased. The bile potassium level greatly exceeded the blood level while the sodium concentration in the bile and in the blood were the same. Bile flow and bilirubin concentration were the same in adrenalectomized as in the control animals. Administration of sodium dehydrocholic acid (100 mg/kg) produced a smaller increase in bile output in adrenalectomized than in non-adrenalectomized animals.