Effect of ML-236b (compactin) on biliary excretion of bile salts and lipids, and on bile flow, in the rat

Kempen, H.J.M.; Lange, Jan de; Holstein, Martha; Wachem, P. van; Havinga, Rick; Vonk, Roelf

doi:10.1016/0005-2760(84)90010-9

Cited by 28 publications

(3 citation statements)

References 22 publications

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“…This apparent discrepancy between enzyme activity and bile acid production can be due to a decreased substrate availability, or to a limited capacity of some other enzyme or transport system involved in bile acid synthesis. A shortage of the product of HMG-CoA reductase, mevalonic acid, can be ruled out in our experimental system: we have shown previously that infusion of mevalonic acid in rats with chronic bile diversion is not accompanied by an increase in bile acid synthesis [24]. These results are in agreement with the observations by Einarsson et al [25,26] that cholesterol 7a-hydroxylase is almost fully saturated under basal conditions and that stimulation of enzyme activity does not lead to major changes in saturation of the enzyme.…”

Section: Discussionmentioning

confidence: 97%

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

Smit

Temmerman

Havinga

et al. 1990

Biochemical Journal

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The present study concerns short- and long-term effects of interruption of the enterohepatic circulation (EHC) on hepatic cholesterol metabolism and biliary secretion in rats. For this purpose, we employed a technique that allows reversible interruption of the EHC, during normal feeding conditions, and excludes effects of anaesthesia and surgical trauma. [3H]Cholesteryl oleate-labelled human low-density lipoprotein (LDL) was injected intravenously in rats with (1) chronically (8 days) interrupted EHC, (2) interrupted EHC at the time of LDL injection and (3) intact EHC. During the first 3 h after interruption of the EHC, bile flow decreased to 50% and biliary bile acid, phospholipid and cholesterol secretion to 5%, 11% and 19% of their initial values respectively. After 8 days of bile diversion, biliary cholesterol output and bile flow were at that same level, but bile acid output was increased 2-3-fold and phospholipid output was about 2 times lower. The total amount of cholesterol in the liver decreased after interruption of the EHC, which was mainly due to a decrease in the amount of cholesteryl ester. Plasma disappearance of LDL was not affected by interruption of the EHC. Biliary secretion of LDL-derived radioactivity occurred 2-4 times faster in chronically interrupted rats as compared with the excretion immediately after interruption of the EHC. Radioactivity was mainly in the form of bile acids under both conditions. This study demonstrates the very rapid changes that occur in cholesterol metabolism and biliary lipid composition after interruption of the EHC. These changes must be taken into account in studies concerning hepatic metabolism of lipoprotein cholesterol and subsequent secretion into bile.

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Section: Discussionmentioning

confidence: 97%

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

Smit

Temmerman

Havinga

et al. 1990

Biochemical Journal

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“…However, this explanation is unlikely because biliary pravastatin concentrations are very low. :'5 I n uitro, HMG-CoA reductase inhibitors have been shown to reduce the activity of 7a-hydroxylase, the rate-limiting enzyme in bile salt synthesis, which is substrate 1imited.l' In case of interrupted enterohepatic circulation, bile salt pool depends on de nouo bile salt ~ynthesis.~"~' In this situation, acute administration of HMG-CoA reductase inhibitors results in decreased bile salt secretion in rats45, 46 and Because the bile salt pool is postulated to be decreased in cholesterol gallstone disease,48 bile salt synthesis and secretion might be susceptible to HMG-CoA reductase inhibitors in gallstone patients. However, in the present study, there was large variability in bile salt concentrations, suggesting that there may be large interindividual variation in susceptibility for HMG-CoA reductase inhibitors with regard to bile salt synthesis, as shown by Mitchell.49 No changes in bile salt molecular species were found.…”

Section: Discussionmentioning

confidence: 99%

The effects of the 3-hydroxy, 3-methylglutaryl coenzyme a reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease

Smit

Erpecum²,

Renooij³

et al. 1995

Hepatology

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3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce biliary cholesterol saturation index (CSI) in duodenal bile in hypercholesterolemic patients and might be useful for gallstone dissolution. However, preliminary data suggest that these drugs are not effective in this respect. We therefore studied 33 patients with radiolucent gallstones in an opacifying gallbladder who were scheduled for elective cholecystectomy. Patients were treated with 40 mg pravastatin day-1 or placebo during the 3 weeks before surgery. Six patients could not be evaluated. Baseline characteristics (age, sex, body mass index, serum cholesterol, and the solitary/multiple gallstone ratio) were similar in both groups. Serum cholesterol fell by 39% in the pravastatin group (P < .001) and remained unchanged in the placebo group. Biliary cholesterol (9.5 +/- 1.3 vs. 14.3 +/- 1.5 mmol/L, P = .026), and phospholipid concentrations (24.8 +/- 3.9 vs. 36.7 +/- 3.9 mmol/L, P = .043) were lower in the pravastatin group. Although bile salt concentrations were lower in the pravastatin group (114 +/- 21 vs. 152 +/- 15 mmol/L), this difference was not significant. CSI was not different between both groups (142 +/- 27% [pravastatin] vs. 113 +/- 6% [placebo], P = NS). Cholesterol crystals were present in fresh bile in 7 of 13 patients in the pravastatin group and in 11 of 14 controls (P = NS). Nucleation time was comparable between the 2 groups (13 +/- 3 vs. 9 +/- 3 days, P = NS). Bile salt species and molecular species of phospholipids determined with high-performance liquid chromatography did not differ either between both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…In that study, however, bile acid secretion decreased as well. 8 Duane et al recently9 found that treatment with simvastatin of 10 patients with non-familial hypercholesterolaemia induced a decrease in mean cholesterol saturation index. The present investigation was designed to determine whether patients treated with pravastatin because of familial hypercholesterolaemia, are at risk for developing cholesterol gall stones.…”

mentioning

confidence: 96%

Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

Linden

Rooy

Jansen

et al. 1990

Gut

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Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p<0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p<0-01) from 1-06 to 075 during treatment with pravastatin. A reduction of 24% (p<0-01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gail stones.

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Effect of ML-236b (compactin) on biliary excretion of bile salts and lipids, and on bile flow, in the rat

Cited by 28 publications

References 22 publications

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

Short- and long-term effects of biliary drainage on hepatic cholesterol metabolism in the rat

The effects of the 3-hydroxy, 3-methylglutaryl coenzyme a reductase inhibitor pravastatin on bile composition and nucleation of cholesterol crystals in cholesterol gallstone disease

Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

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