| Possible protective role of pregnenolone-16 alpha-carbonitrile in lithocholic acid-induced hepatotoxicity through enhanced hepatic lipogenesis. | |
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MedLine Citation:
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PMID: 20359477 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Lithocholic acid (LCA) feeding causes both liver parenchymal and cholestatic damages in experimental animals. Although pregnenolone-16 alpha-carbonitrile (PCN)-mediated protection against LCA-induced hepatocyte injury may be explained by induction of drug metabolizing enzymes, the protection from the delayed cholestasis remains incompletely understood. Thus, the PCN-mediated protective mechanism has been studied from the point of modification of lipid metabolism. At an early stage of LCA feeding, an imbalance of biliary bile acid and phospholipid excretion was observed. Co-treatment with PCN reversed the increase in serum alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities and hepatic hydrophobic bile acid levels. LCA feeding decreased hepatic mRNA levels of several fatty acid- and phospholipid-related genes before elevation of serum ALT and ALP activities. On the other hand, PCN co-treatment reversed the decrease in the mRNA levels and hepatic levels of phospholipids, triglycerides and free fatty acids. PCN co-treatment also reversed the decrease in biliary phospholipid output in LCA-fed mice. Treatment with PCN alone increased hepatic phospholipid, triglyceride and free fatty acid concentrations. Hepatic fatty acid and phosphatidylcholine synthetic activities increased in mice treated with PCN alone or PCN and LCA, compared to control mice, whereas these activities decreased in LCA-fed mice. These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity. |
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Authors:
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Masaaki Miyata; Masahiro Nomoto; Fumiaki Sotodate; Tomohiro Mizuki; Wataru Hori; Miho Nagayasu; Shinya Yokokawa; Shin-ichi Ninomiya; Yasushi Yamazoe |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-30 |
Journal Detail:
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Title: European journal of pharmacology Volume: 636 ISSN: 1879-0712 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-10 Completed Date: 2010-08-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 145-54 Citation Subset: IM |
Copyright Information:
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(c) 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan. miyata@mail.pharm.tohoku.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biliary Tract / drug effects, metabolism Biological Markers / blood, metabolism Fatty Acids / biosynthesis, blood, metabolism Female Gene Expression Profiling Hepatocytes / drug effects*, metabolism, pathology Lipogenesis / drug effects* Lithocholic Acid / toxicity* Liver / drug effects*, metabolism*, pathology Liver Diseases / blood, metabolism, pathology, prevention & control* Mice Mice, Inbred C57BL Phosphatidylcholines / biosynthesis, blood, metabolism Pregnenolone Carbonitrile / pharmacology* Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Biological Markers; 0/Fatty Acids; 0/Phosphatidylcholines; 1434-54-4/Pregnenolone Carbonitrile; 434-13-9/Lithocholic Acid |
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