INCREASED SKIN TUMORIGENESIS IN MICE LACKING PI CLASS GLUTATHIONE S-TRANSFERASES

The activity of chemical carcinogens is a complex balance between meta bolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of thes e proteins may have profound effects on carcinogenic activity, althoug h it has proved impossible to ascribe the observed effects to the acti vity of a single protein. GstP appears to play a very important role i n carcinogenesis, although the precise nature of its involvement is un clear. We have deleted the murine GstP gene cluster and established th e effects on skin tumorigenesis induced by the polycyclic aromatic hyd rocarbon 7,12-dimethylbenz anthracene and the tumor promoting agent 12 -O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significa nt increase in the number of papillomas was found in the GstP1/P2 null mice [GstP1/P2((-/-)), mice, 179 papillomas, mean 9.94 per animal vs. GstP1/P2((+/+)), mice, 55 papillomas, mean 2.89 per animal, (P < 0.00 1)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect o n tumorigenicity, and demonstrates that GstP may be an important deter minant in cancer susceptibility, particularly in diseases where exposu re to polycyclic aromatic hydrocarbons is involved, for instance in ci garette smoke-induced lung cancer.