Structure-Toxicity Relationships
ACTIVTox provides structural information related to toxicity
A common problem in drug development is that one member of a structural series displays toxicity that is not seen in other members of the family. Oftentimes, this is not discovered until late in the development process, causing unnecessary delays in bringing the new medicine to market. ACTIVTox provides a system in which to identify structure-based hepatotoxicity early in the process, when it can be easily and comparatively inexpensively remedied.
We have several examples of structure related toxicity to show you, click on the links to the right under Structure Families to see other examples.
Thiazolidinediones
Figure 1. Structure of thiazolidinediones.
The thiazolidinediones (TZD) were a new class of antidiabetic compound when troglitazone was first introduced. They are believed to work through the PPARγ receptor to control insulin resistance and reduce blood glucose (1). Troglitazone had the unfortunate side effect of causing severe, sometimes fatal, liver disease in certain patients, leading to its market withdrawal. Figure 1 shows the structure of four TZDs. Two of these compounds, pioglitazone and rosiglitazone have remained on the market and are not known to cause liver dysfunction. When we examined each of the four compounds shown in Fig. 1 in the ACTIVTox hepatotoxicity assay, troglitazone was clearly more toxic.
Figure 2. Troglitazone is more hepatotoxic than other TZDs.
Procedure
Each of the four compounds was incubated with the cells for 48 hrs at 100µM. All tests were performed in triplicate with appropriate controls on each plate. Cell death was measured using LDH release.
ACTIVTox recognizes troglitazone as more toxic
Figure 2 shows that troglitazone is clearly more toxic that the other TZDs when tested in the ACTIVTox hepatotoxicity assay. In a series of other assays, including inhibition of cell proliferation, CYP3A induction and ATP content, troglitazone was the only compound that was positive in each of the assays at this concentration.
Other examples of structurally relevant toxicity information is available from Stem Cell Innovations.
References
- Staels, B. and Fruchart, JC (2005) Therapeutic role of peroxisome proliferatorsactivated receptor agonists. Diabetes 54, 2460 – 2470.
