Thiazolidinediones are a class of Peroxisome Proliferator Activated Receptor gamma (PPAR gamma) agonists that reduce insulin resistance in type 2 diabetic patients. Although no detectable hepatic toxicity has been evidenced in animal studies during preclinical trials, these molecules have nevertheless induced hepatic adverse effects in some treated patients. The mechanism(s) of hepatotoxicity remains equivocal. Several studies have been conducted using PCR analysis and microarray technology to identify possible target genes and here we review the data obtained from various in vivo and in vitro experimental models. Although PPAR gamma is expressed at a much lower level in liver than in adipose tissue, PPAR gamma agonists exert various PPAR gamma-dependent effects in liver in addition to PPAR gamma-independent effects. Differences in effects are dependent on the choice of agonist and experimental conditions in rodent animal studies and in rodent and human liver cell cultures. These effects are much more pronounced in obese and diabetic liver. Moreover, our own recent studies have shown major interindividual variability in the response of primary human hepatocyte populations to troglitazone treatment, supporting the occurrence of hepatotoxicity in only some individuals.
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F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Funk, C
Ponelle, C
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F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Ponelle, C
Scheuermann, G
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F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Scheuermann, G
Pantze, M
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F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
机构:Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Goyak, Katy M. O.
Johnson, Mary C.
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机构:Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Johnson, Mary C.
Strom, Stephen C.
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Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USAPenn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Strom, Stephen C.
Omiecinski, Curtis J.
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Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USAPenn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
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Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA
Grommes, C
Landreth, GE
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Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA
Landreth, GE
Heneka, MT
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Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA
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F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Funk, C
Ponelle, C
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h-index: 0
机构:
F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Ponelle, C
Scheuermann, G
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h-index: 0
机构:
F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
Scheuermann, G
Pantze, M
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h-index: 0
机构:
F Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, SwitzerlandF Hoffmann La Roche & Co Ltd, Div Pharmaceut, Non Clin Dev Drug Safety, CH-4070 Basel, Switzerland
机构:Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Goyak, Katy M. O.
Johnson, Mary C.
论文数: 0引用数: 0
h-index: 0
机构:Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Johnson, Mary C.
Strom, Stephen C.
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h-index: 0
机构:
Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USAPenn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
Strom, Stephen C.
Omiecinski, Curtis J.
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h-index: 0
机构:
Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USAPenn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16802 USA
机构:
Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA
Grommes, C
Landreth, GE
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h-index: 0
机构:
Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA
Landreth, GE
Heneka, MT
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h-index: 0
机构:
Case Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USACase Western Reserve Univ, Sch Med, Dept Neurosci, Alzheimer Res Lab, Cleveland, OH 44106 USA