Polyamines modulate carcinogen-induced mutagenesis in vivo.
Elevated polyamine levels as a consequence of targeted overexpression of ornithine decarboxylase (ODC) to murine skin enhance susceptibility to tumorigenesis in this tissue. A possible mechanism for the enhanced susceptibility phenotype is an increased sensitivity of tissues with elevated polyamine levels to the mutagenic action of carcinogens. To test this hypothesis, a transgenic mouse model containing the Big Blue transgene and also expressing a K6/ODC transgene was developed. Incorporation of the K6/ODC transgene into the Big Blue model did not affect the spontaneous lacI mutant frequency in either skin or epidermis of the double-transgenic mice. After skin treatment with single doses of either 7,12-dimethylbenz[a]anthracene or N-methyl-N'-nitro-N-nitrosoguanidine, however, the mutant frequency was significantly increased in the skin of double-transgenic Big Blue;K6/ODC mice compared to Big Blue controls. The increases in mutant frequency were clearly due to ODC transgene activity, since treatment of mice with the ODC inhibitor, alpha-difluoromethylornithine, completely abolished the difference in mutant frequencies between double-transgenic and Big Blue mice. These results demonstrate that intracellular polyamine levels modulate mutation induction following carcinogen exposure.
Wallon
U Margaretha
UM
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA. wallonm@mlhs.org
O'Brien
Thomas G
TG
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis; D009154:Mutation; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced*
D002273:Carcinogens; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D008769:Methylnitronitrosoguanidine; D015127:9,10-Dimethyl-1,2-benzanthracene; D009955:Ornithine Decarboxylase