Solving the Polymorphism Problem

In a previous blog, I pointed out how genetic polymorphisms can complicate the testing of new drugs on animals, despite the fact that we have some enzymes in common with rats, mice and other test organisms. Over the years, as gene sequencing methods have been perfected and whole genomes sequenced, scientists have come up with creative ways to improve drug fate studies. One solution is to develop mouse lines expressing human genes. According to Powley et al. (2009) the benefits are three-fold: better scientific relevance of the animal study, decreased costs and a possible decrease in the number of test subjects (i.e. mice) needed per study. In another laboratory, chimeric mice with humanized livers, generated by xenotransplantation of human hepatocytes into the mice, have been created, and the properties of the enzymes (such as specific activity, Vmax and Km values) compared to the donor humans with promising results (Katoh et al. 2008).

No matter what the technique though, the mouse models remain just that – models. Many other factors including the expression of other enzymes and minor metabolites, and relative concentrations of each, will affect the outcome of a pharmacogenetic study.

_Sources:

Powley, MW et al. 2009. Safety assessment of drug metabolites: implications of regulatory guidance and potential application of genetically engineered mouse models that express human P450s. Chem. Res. Toxicol. 22(2):257-62.

Katoh, M. et al. 2008. Chimeric mice with humanized liver. Toxicology 246(1):9-17.