Document Detail


An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells.
MedLine Citation:
PMID:  19332084     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicity is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC(50) values 100 microM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.
Authors:
Fozia Noor; Jens Niklas; Ursula Müller-Vieira; Elmar Heinzle
Related Documents :
2476674 - Multilayered keratinocyte culture used for in vitro toxicology.
2862864 - Antileukemic effect of coral-prostanoids clavulones from the stolonifer clavularia viri...
9414104 - Cell cycle dependent toxicity of an amphiphilic synthetic peptide.
19002174 - Isothiocyanate nb7m causes selective cytotoxicity, pro-apoptotic signalling and cell-cy...
2476674 - Multilayered keratinocyte culture used for in vitro toxicology.
12429734 - Cisplatin sensitivity in hmbg1-/- and hmbg1+/+ mouse cells.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-28
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  237     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-15     Completed Date:  2009-06-09     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  221-31     Citation Subset:  IM    
Affiliation:
Biochemical Engineering Institute, Saarland University, Campus A 1.5, D-66123 Saarbruecken, Germany. fozia.noor@mx.uni-saarland.de
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Cytotoxins / toxicity*
Drug Evaluation, Preclinical / methods*
Hepatocytes / drug effects*
Humans
Male
Rats
Rats, Sprague-Dawley
Rats, Wistar
Sensitivity and Specificity
Time Factors
Chemical
Reg. No./Substance:
0/Cytotoxins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  The neuropeptides CCK and NPY and the changing view of cell-to-cell communication in the taste bud.
Next Document:  Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights from an experimental...