A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of genotoxic damage

The tumor suppressor gene p53 encodes a nuclear phosphoprotein which iscritical for cell cycle control and prevention of uncontrolled cellproliferation that can lead to cancer. Previous studies have shown thatcells respond to DNA damage by increasing their levels of p53, which thenacts to prevent replication of damaged DNA. This study examined the effectson p53 protein levels of several different categories of chemicalcarcinogens. N-Methyl-N'-nitro-nitrosoguanidine and N-ethyl-N- nitrosourea,two direct-acting genotoxic (DNA-reactive) carcinogens, caused p53induction as early as 2 h following treatment, with peak increases within4-12 h. Aflatoxin B1 and 2-acetylaminofluorene, indirect-acting genotoxiccarcinogens, caused a later induction of p53, with the peak increaseappearing between 16 and 24 h following treatment. These observationsdemonstrate a correlation between p53 induction pattern and DNA damagingmechanism of genotoxins. Phenol, diethylstilbestrol and ethylacrylate alsoinduced increases in cellular p53. The half-life of p53 protein wasincreased in cells treated with genotoxic agents. On the other hand, theepigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, aswell as two substances generally considered to be non-carcinogens,dimethylsulfoxide and benzethonium chloride, had no effect on p53 proteinlevels of treated cells. Measurement of the cytotoxic effects of each ofthese chemicals led to the conclusion that p53 protein induction is not ageneral, non- specific consequence of the cytotoxic effect of thesegenotoxins. These results suggest that measurement of p53 protein inductionmay be an effective tool to identify environmental genotoxins.