Human beings are exposed to a multitude of
carcinogens in their environment, and most
cancers are considered to be chemically induced. Here we examined differences in genetic alterations in rat forestomach
tumors induced by repeated exposure to a genotoxic
carcinogen,
N-methyl-N'-nitro-N-nitrosoguanidine (
MNNG) or N-
methylnitrosourethane (MNUR), and chronic treatment with a non-genotoxic
carcinogen,
butylated hydroxyanisole (
BHA) or
caffeic acid (CA). A total of 132, 6-week-old male F344 rats were employed. Forty rats were treated with
MNNG by intragastric administration at a dose of 20 mg/kg body wt once a week for 32 weeks, and 20 rats received 20 p.p.m. MNUR in their
drinking water for 48 weeks. Further groups of 20 animals were administered 2%
BHA or 2% CA in the diet for 104 weeks. The remaining rats were maintained without any supplement as controls. Multiple forestomach
tumors were observed in all rats of the
MNNG-, MNUR-,
BHA- and CA-treated groups. Histopathologically, MNUR- and CA-treated groups showed almost the same pattern. On polymerase chain reaction-single strand conformation polymorphism analysis, H-ras and p53 gene mutations were observed at high and relatively low frequencies, respectively, in forestomach
tumors induced by
MNNG and MNUR. Most H-ras gene mutations were G-->A transitions in
codons 7 and 12 of exon 1. On the other hand, forestomach
tumors due to the non-genotoxic
carcinogens,
BHA and CA, had almost no mutations of the H-ras and p53 genes. Moreover, relative overexpression of
cyclin D1 and p53 was detected in forestomach
tumors induced by the genotoxic
carcinogens, while their non-genotoxic counterparts had a tendency to show low expression of those molecules. Mutations of the
beta-catenin gene were not detected in any group. The present study demonstrates that rat forestomach
tumors induced by genotoxic and non-genotoxic
carcinogens have different underlying genetic alterations, even if their pathological features are similar.