Predicting drug metabolism-dependent toxicity for humans with a genetically engineered cell battery.
This paper covers the presentation of an invited lecture - the FRAME Annual Lecture - given in London on 8 November 2006. Investigating the metabolism of chemicals in general, and of drugs and pollutants in particular, is of key importance to understanding pharmacological and toxicological effects. Over more than 15 years, the genes encoding the enzymes involved, have been individually cloned and expressed after gene transfer into V79 Chinese hamster cells, yielding a collection of cell lines - the so called V79 Cell Battery. With this technology, it has become possible to study the relevant enzymes individually, thus avoiding complex in vivo situations. By cloning genes from different species, including humans, species-species comparison became possible, yielding results of immediate predictive value for humans. Since V79 cells had already been approved by the OECD for toxicity studies since the 1980s, the metabolically competent V79 cell lines are of even greater value, as metabolism and toxicity testing are linked in the very same cells in a highly defined fashion. The results obtained so far with the genetically engineered V79 cell lines justify their acceptance as alternatives to animal experimentation in drug development and in the toxicity testing of chemicals, serving the goals of the Three Rs and, in particular, the most important R: Replacement.
Doehmer
Johannes
J
GenPharmTox BioTech AG, Fraunhoferstr. 9, D-82152, Planegg/Martinsried, Germany. johannes.doehmer@genpharmtox.de
D000826:Animal Testing Alternatives; D000818:Animals; D002460:Cell Line; D002477:Cells / Q000187:drug effects* / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1; D064420:Drug-Related Side Effects and Adverse Reactions; D005399:Fishes; D005449:Fluorenes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity; D018675:Toxicity Tests / Q000379:methods*
D005449:Fluorenes; D004364:Pharmaceutical Preparations; C012177:2-aminofluorene; D019363:Cytochrome P-450 CYP1A1