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Increased skin tumorigenesis in mice lacking pi class glutathione S-transferases
C J Henderson1, A G Smith, J Ure
1Imperial Cancer Research Fund Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom.
Abstract:
The activity of chemical carcinogens is a complex balance between metabolic activation by cytochrome P450 monooxygenases and detoxification by enzymes such as glutathione S-transferase (GST). Regulation of these proteins may have profound effects on carcinogenic activity, although it has proved impossible to ascribe the observed effects to the activity of a single protein. GstP appears to play a very important role in carcinogenesis, although the precise nature of its involvement is unclear. We have deleted the murine GstP gene cluster and established the effects on skin tumorigenesis induced by the polycyclic aromatic hydrocarbon 7, 12-dimethylbenz anthracene and the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate. After 20 weeks, a highly significant 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 < 0.001)]. This difference in tumor incidence provides direct evidence that a single gene involved in drug metabolism can have a profound effect on tumorigenicity, and demonstrates that GstP may be an important determinant in cancer susceptibility, particularly in diseases where exposure to polycyclic aromatic hydrocarbons is involved, for instance in cigarette smoke-induced lung cancer.
Insights
Deleting the glutathione S-transferase P (GstP) gene cluster significantly increased skin tumors in mice exposed to carcinogens. This highlights GstP
Area of Science:
- Biochemistry
- Toxicology
- Genetics
Background:
- Chemical carcinogen activity involves a balance between metabolic activation and detoxification.
- Glutathione S-transferase P (GstP) is implicated in carcinogenesis, but its exact role is unclear.
Purpose of the Study:
- To investigate the role of GstP in skin tumorigenesis by deleting the murine GstP gene cluster.
- To determine the effect of GstP deficiency on tumor development induced by specific carcinogens.
Main Methods:
- Deletion of the murine GstP gene cluster to create GstP1/P2 null mice.
- Induction of skin tumorigenesis using 7,12-dimethylbenz anthracene and 12-O-tetradecanoylphorbol-13-acetate.
- Quantification of papilloma incidence in GstP1/P2 null and wild-type mice after 20 weeks.
Main Results:
- GstP1/P2 null mice showed a highly significant increase in papilloma number (179 vs. 55) compared to wild-type mice.
- The mean number of papillomas per animal was significantly higher in GstP1/P2 null mice (9.94 vs. 2.89).
- P-value < 0.001 indicates a statistically significant difference in tumor incidence.
Conclusions:
- GstP plays a critical role in determining susceptibility to chemically induced skin tumorigenesis.
- A single gene involved in drug metabolism can profoundly impact tumorigenicity.
- GstP is a key determinant in cancer susceptibility, especially in cases involving polycyclic aromatic hydrocarbon exposure, such as in lung cancer from cigarette smoke.