| Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors. | |
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MedLine Citation:
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PMID: 15163549 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hepatotoxicity is the major complaint during therapy with lipid-lowering agents such as statins, although the cellular mechanisms underlying the statin-induced liver injury are not fully understood. Using cultured human hepatocytes, we investigated the effects of lipophilic as well as hydrophilic statins on the cell viability. Lipophilic statins, including simvastatin, lovastatin, cerivastatin, fluvastatin and atorvastatin, reduced the viability of hepatocytes as assessed by the mitochondrial enzyme activity to reduce WST-8, however, a hydrophilic pravastatin did not cause cell injury. The simvastatin-induced loss of cell viability was attenuated by mevalonate or geranylgeranyl pyrophosphate. Simvastatin-induced DNA fragmentation and increased the number of cells stained with annexin V and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, both of which were reversed by caspase inhibitors such as zDEVD-fmk, zLEHD-fmk and zIETD-fmk. Consistent with these data, the activities of caspase-3, caspase-9 and caspase-8 were elevated by simvastatin. Simvastatin reduced the protein content and mRNA expression for bcl-2 without affecting bax mRNA expression. On the other hand, both lipophilic and hydrophilic statins significantly reduced the content of endogenous cholesterol. These findings suggest that lipophilic statins cause an apoptotic injury in human hepatocytes by stimulating caspase-3 subsequent to the activation of caspase-9 and caspase-8, in which the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may be involved. |
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Authors:
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Toshio Kubota; Koji Fujisaki; Yoshinori Itoh; Takahisa Yano; Toshiaki Sendo; Ryozo Oishi |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Biochemical pharmacology Volume: 67 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2004 Jun |
Date Detail:
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Created Date: 2004-05-27 Completed Date: 2004-07-09 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 2175-86 Citation Subset: IM |
Affiliation:
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Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Annexin A5 / chemistry Apoptosis* Caspase 3 Caspases / metabolism Cholesterol / metabolism Enzyme Inhibitors / pharmacology Hepatocytes / drug effects*, metabolism Heptanoic Acids / pharmacology Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology* In Situ Nick-End Labeling Pravastatin / pharmacology Proto-Oncogene Proteins c-bcl-2 / metabolism Pyrroles / pharmacology RNA, Messenger / drug effects, metabolism Simvastatin / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Annexin A5; 0/Enzyme Inhibitors; 0/Heptanoic Acids; 0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrroles; 0/RNA, Messenger; 110862-48-1/atorvastatin; 57-88-5/Cholesterol; 79902-63-9/Simvastatin; 81093-37-0/Pravastatin; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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