O^6-Methylguanine-DNA Methyltransferase Protects Against Nitrosamine-Induced Hepatocarcinogenesis

We previously generated transgenic C3H/HeN mice by introducing the Escherichia coli O6-methylguanine-DNA methyltransferase (MGMT, DNA-O6-methylguanine:protein-L-cysteine S-methyltransferase, EC2.1.1.63) gene, ada, attached to the Chinese hamster metallothionein I gene promoter. One transgenic mouse line expressing both ada-specific mRNA and Ada protein could be propagated over many generations in a homozygous state with respect to the integrated DNA. Liver extracts from transgenic homozygous mice have consistently demonstrated about 3 times the control activity of normal mice. Furthermore, in the transgenic homozygotes treated with ZnSO4, activity is increased to 6-8 times the normal level in mice and is equivalent to that for man. To examine whether these increased levels of MGMT activity can actually decrease the susceptibility of animals to N-nitroso compounds, we studied liver carcinogenesis in our transgenic mice expressing high amounts of MGMT. Groups of transgenic and nontransgenic mice, each comprising about 200 suckling animals (14 +/- 1 days old), were divided each into eight subgroups, providing paired groups of transgenic and nontransgenic mice. They received an i.p. injection of ZnSO4 to induce MGMT, and 10 hr thereafter were given an i.p. injection of either dimethylnitrosamine or diethylnitrosamine. Liver tumor development was quantitatively assessed at 7-11 months. Here, we report statistically significant reduction of tumor formation in transgenic mice of four of the six paired groups that received treatment. The remaining two demonstrated results in line with dose dependence. Therefore, our data indicate that MGMT can indeed protect animals from low-dose exposure to environmental alkylating carcinogens.