The use of glutathione transferase-knockout mice as pharmacological and toxicological models

ADME/Tox studies are of increasing importance because of the necessity to eliminate poor drug candidates early in the development pipeline. The glutathione S-transferases (GSTs) are a family of phase II enzymes that have been shown to play a significant role in the disposition of a wide range of drugs and other xenobiotics. Several GST-knockout mice strains have been developed that can potentially be used in ADME/Tox studies. So far, mice have been generated with deficiencies of mGSTP1/2, mGSTA4-4, mGSTZ1-1, mGSTM1-1, mGSTO1-1 and mGSTS1-1, but studies of drug metabolism in these strains have been limited. As there are 21 recognised GST genes in mice there is potential for many more strains to be made. However, a review of the available data suggests that because of differences in the evolution of the GST gene family between rodents and humans, only some knockout strains can provide insights relevant to human drug metabolism. It is concluded that, of the strains generated so far, only those deficient in mGSTP1-1, mGSTA4-4, mGSTO1-1 and mGSTZ1-1 have direct human orthologues and can be considered as human models. In contrast, there may not be appropriate orthologues of some enzymes, such as hGSTM1-1, that are known to be of relevance in drug metabolism.