Caenorhabditis elegans as model system for rapid toxicity assessment of pharmaceutical compounds.
BACKGROUND
The model organism Caenorhabditis elegans is widely used for genetic studies as well as a living biomonitor in ecotoxicology. In this study, we investigated whether C. elegans may represent a suitable model for rapid preliminary toxicity studies of pharmaceutical compounds.


METHODS
For this purpose, we used the EGFR kinase inhibitors BIBU1361, BIBX1382, and an inactive chemical analogue BIBU1476. As a first parameter to score for toxicity, we determined lethality of the wild-type C. elegans strain N2 (Bristol) in the presence of the compounds. The transgenic C. elegans strain PC72 (lacZ, heat shock protein-16 [hsp-16] construct) was used as a report organism for toxic effects. PC72 expresses beta-Galactosidase which is induced by hsp-16 in direct response when exposed to toxic compounds. The expression of beta-Galactosidase in cells was subsequently visualized by histochemical staining with X-Gal.


RESULTS
A rank order of potency with respect to lethality was established: BIBU1361>BIBX1382>>BIB1476. The induction of beta-Galactosidase was concentration-dependent for each compound and demonstrated the same order of potency as observed for lethality. Furthermore, these compounds showed the same order for lethality in rodents, the first requirement of validation.


CONCLUSIONS
These results indicate that wild-type C. elegans and the transgenic strain PC72 are both suitable models to determine the toxicity of pharmaceutical compounds. This approach allows for an easy and fast ranking of compound toxicity, which may lead to a more rational choice for further in vivo tests.
Dengg
Marlene
M
Boehringer Ingelheim Austria GmbH, Dr. Boehringer-Gasse 5-11, Vienna 1121, Austria.
van Meel
Jacques C A
JC
D023401:Animal Use Alternatives; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006651:Histocytochemistry; D007928:Lethal Dose 50; D008136:Longevity / Q000187:drug effects; D023421:Models, Animal; D009930:Organic Chemicals / Q000633:toxicity*; D030781:Organisms, Genetically Modified; D010880:Piperidines / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D001616:beta-Galactosidase / Q000096:biosynthesis
C495482:(3-chloro-4-fluoro-phenyl)-(6-(4-diethylaminomethyl-piperidin-1yl)-pyrimido(5,4-d)pyrimidin-4-yl)amine; C423062:BIBX 1382BS; D029742:Caenorhabditis elegans Proteins; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D009930:Organic Chemicals; D010880:Piperidines; D011743:Pyrimidines; C108431:hsp-16.2 protein, C elegans; D001616:beta-Galactosidase