A multicentre study of acute in vitro cytotoxicity in rat liver cells

Fautrel, Alain; Chesné, Christophe; Guillouzo, André; Sousa, Georges de; Placidi, M; Rahmani, Roger; Braut, Françoise; Pichon, J.; Hoellinger, H.; Vintèzou, Pascale; Diarte, I.; Melción, C.; André, Carl; Lorenzon, Giocondo; Benicourt, Marc; Vannier, Bernard; Fournex, R.; Peloux, A.F.; Bichet, N.; Gouy, D.; Cano, J. P.; Lounes, R.

doi:10.1016/0887-2333(91)90090-z

Cited by 53 publications

(19 citation statements)

References 8 publications

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“…A single end point is usually sufficient to estimate irreversible injury induced by toxic compounds. For example, comparable results were obtained with primary rat hepatocyte cultures exposed to various compounds by measuring extracellular and total LDH ratio, total cellular protein content, MTT assay, and neutral red uptake (174). When metabolic competence is evaluated, IC50 values can be much lower than those calculated from parameters of plasma membrane integrity and false negative compounds have been reported.…”

Section: However Survival and Metabolic Compe-supporting

confidence: 50%

Liver cell models in in vitro toxicology.

Guillouzo

1998

Environ Health Perspect

297

125

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In vitro liver preparations are increasingly used for the study of hepatotoxicity of chemicals. In recent years their actual advantages and limitations have been better defined. The cell models, slices, and mainly primary hepatocyte cultures, appear to be the most powerful in vitro systems, as liver-specific functions and responsiveness to inducers are retained either for a few days or several weeks depending on culture conditions. Maintenance of phase and phase 11 xenobiotic metabolizing enzyme activities allows various chemical investigations to be performed, including determination of kinetic parameters, metabolic profile, interspecies comparison, inhibition and induction effects, and drug-drug interactions. In vitro liver cell models also have various applications in toxicology: screening of cytotoxic and genotoxic compounds, evaluation of chemoprotective agents, and determination of characteristic liver lesions and associated biochemical mechanisms induced by toxic compounds. Extrapolation of the results to the in vivo situation remains a matter of debate. Presently, the most convincing applications of liver cell models are the studies on different aspects of metabolism and mechanisms of toxicity. For the future, there is a need for better culture conditions and differentiated hepatocyte cell lines to overcome the limited availability of human liver tissues. In addition, strategies for in vitro analysis of potentially toxic chemicals must be better defined. Environ Health Perspect 106(Suppl 2):511-532 (1998). http.//ehpnetl.niehs.nih.gov/docs/1998/Suppl-2/51 1-532guillouzo/abstract.html

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Section: However Survival and Metabolic Compe-supporting

confidence: 50%

Liver cell models in in vitro toxicology.

Guillouzo

1998

Environ Health Perspect

297

125

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“…The primary cultured hepatocytes also appear to be the most powerful system for in vitro toxicology: screening of cytotoxic and genotoxic compounds, evaluation of chemoprotective agents, and determination of characteristic liver lesions and associated biochemical mechanisms induced by toxic compounds. This explains why numerous toxicity studies have been performed with isolated hepatocytes, either in suspension or in a primary culture (Ekwall and Acosta, 1982;Faber et al, 1988;Fautrel et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines.

et al. 2002

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-We investigated and compared the cytotoxicity of 16 reference compounds in four in vitro systems: primary cultured rat hepatocytes, hepatoma HepG2 cell line, non-hepatic HeLa and Balb/c 3T3 cell lines. After 24 hr of exposure to the test compounds, the water-soluble tetrazolium salts WST-1 assay was used as an endpoint to evaluate cytotoxicity. Acetaminophen, diclofenac sodium cyclophosphamide and disulfiram displayed from 2 to more than10 times higher IC 50 values in three cell lines than in rat primary cultured hepatocytes. The cytotoxic effects of aspirin, amiodarone, clorfibiric acid, chlorpromazine, erythomycin, lithocholic acid, cisplatin and quinidine in rat hepatocytes were similar or 2 times stronger than those observed in cell lines. Ketoconazole resulted in the lowest IC 50 value in the HeLa cell line. The data suggested that the compounds which are known to be metabolism-mediated liver toxicants have a differential hepatotoxicity in vitro and that primary cultured rat hepatocytes could represent a valuable tool for both screening and study of the effects of bio-transformation on the cytotoxicity of new chemical entities and xenobiotics in vitro.

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“…The liver is one of the important organs for toxicological evaluation from the aspects of the major metabolism site of xenobiotics as a primary target of drugs (Fautrel et al, 1991;Alden et al, 1999). More sensitive and reliable endpoints as toxicologically responsible biomarkers were required for setting the high throughput screening system of hepatotoxicity in the early stage of drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Identification of Oxidative Stress-Related Proteins for Predictive Screening of Hepatotoxicity Using a Proteomic Approach

et al. 2005

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-We investigated the effects of three hepatotoxicants, acetaminophen (APAP), amiodarone (AD) and tetracycline (TC), on protein expression in primary cultured rat hepatocytes with toxicoproteomic approach, which is two-dimensional gel electrophoresis (2DE) and mass spectrometry. The objectives of this study were to search for alternative toxicity biomarkers which could be detected with high sensitivity prior to the appearance of morphological changes or alterations of analytical conventional biomarkers. The related proteins in the process of cell degeneration/necrosis such as cell death, lipid metabolism and lipid/carbohydrate metabolism were mainly affected under exposure to APAP, AD and TC, respectively. Among the differentially expressed proteins, several oxidative stress-related proteins were clearly identified after 24-hr exposure, even though they were not affected for 6-hr exposure. They were glutathione peroxidase (GPX) as a down-regulated protein as well as peroxiredoxin 1 (PRX1) and peroxiredoxin 2 (PRX2) as up-regulated proteins, which are known to serve as antioxidative enzymes in cells. These findings suggested that the focused proteins, GPX and PRXs, could be utilized as biomarkers of hepatotoxicity, and they were useful for setting high throughput screening methods to assess hepatotoxicity in the early stage of drug discovery.

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A multicentre study of acute in vitro cytotoxicity in rat liver cells

Cited by 53 publications

References 8 publications

Liver cell models in in vitro toxicology.

Liver cell models in in vitro toxicology.

Advantages of in vitro cytotoxicity testing by using primary rat hepatocytes in comparison with established cell lines.

Identification of Oxidative Stress-Related Proteins for Predictive Screening of Hepatotoxicity Using a Proteomic Approach

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