O6-METHYLGUANINE-DNA METHYLTRANSFERASE PROTECTS AGAINST NITROSAMINE-INDUCED HEPATOCARCINOGENESIS

We previously generated transgenic C3H/HeN mice by introducing the Esc herichia Coli O6-methylguanine-DNA methyltransferase (MGMT, DNA-O6-met hylguanine:protein-L-cysteine S-methyltransferase, EC2.1.1.63) gene, a da, attached to the Chinese hamster metallothionein I gene promoter. O ne transgenic mouse line expressing both ada-specific mRNA and Ada pro tein could be propagated over many generations in a homozygous state w ith respect to the integrated DNA. Liver extracts from transgenic homo zygous mice have consistently demonstrated about 3 times the control a ctivity of normal mice. Furthermore, in the transgenic homozygotes tre ated with ZnSO4, activity is increased to 6-8 times the normal level i n mice and is equivalent to that for man. To examine whether these inc reased levels of MGMT activity can actually decrease the susceptibilit y of animals to N-nitroso compounds, we studied liver carcinogenesis i n our transgenic mice expressing high amounts of MGMT. Groups of trans genic and nontransgenic mice, each comprising about 200 suckling anima ls (14 +/- 1 days old), were divided each into eight subgroups, provid ing paired groups of transgenic and nontransgenic mice. They received an i.p. injection of ZnSO4 to induce MGMT, and 10 hr thereafter were g iven an i.p. injection of either dimethyinitrosamine or diethylnitrosa mine. Liver tumor development was quantitatively assessed at 7-11 mont hs. Here, we report statistically significant reduction of tumor forma tion in transgenic mice of four of the six paired groups that received treatment. The remaining two demonstrated results in line with dose d ependence. Therefore, our data indicate that MGMT can indeed protect a nimals from low-dose exposure to environmental alkylating carcinogens.