Abstract | BACKGROUND AND AIMS: METHODS: We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30-60 mg/kg/day) or Ro 48-8071 (30-100 mg/kg/day), while ingesting chow or the lithogenic diet. RESULTS: Both agents reduced the gall stone prevalence rate from 73% to 17% in C57L/J mice, inhibited HMGR activity, and decreased hepatic cholesterol concentrations without appreciably influencing biliary cholesterol secretion. In C57L as well as AKR mice, both agents increased biliary phospholipid (which is mostly phosphatidylcholine) secretion rates and at the highest doses effectively reduced the biliary cholesterol saturation index. CONCLUSIONS:
Cholesterol biosynthesis inhibitors acting distally to squalene do not reduce biliary cholesterol secretion rates despite reductions in cholesterol biosynthesis and hepatocellular levels. However, they effectively prevent gall stone formation through stimulation of pathways that lead to enhanced biliary phospholipid secretion.
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Authors | G A Clarke, G Bouchard, B Paigen, M C Carey |
Journal | Gut
(Gut)
Vol. 53
Issue 1
Pg. 136-42
(Jan 2004)
ISSN: 0017-5749 [Print] England |
PMID | 14684588
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Anticholesteremic Agents
- Benzophenones
- Enzyme Inhibitors
- Phospholipids
- Thiophenes
- Tu 2208
- Ro 48-8071
- Cholesterol
- Oxygenases
- Squalene Monooxygenase
- Intramolecular Transferases
- lanosterol synthase
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Topics |
- Animals
- Anticholesteremic Agents
(therapeutic use)
- Benzophenones
(therapeutic use)
- Bile
(metabolism)
- Bile Canaliculi
(metabolism)
- Cholelithiasis
(genetics, metabolism, prevention & control)
- Cholesterol
(biosynthesis, blood)
- Enzyme Inhibitors
(therapeutic use)
- Genetic Predisposition to Disease
- Intramolecular Transferases
(antagonists & inhibitors)
- Lipid Metabolism
- Liver
(metabolism)
- Male
- Mice
- Mice, Inbred AKR
- Mice, Inbred C57BL
- Oxygenases
(antagonists & inhibitors)
- Phospholipids
(metabolism)
- Squalene Monooxygenase
- Thiophenes
(therapeutic use)
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