Modification of chemical carcinogenesis by antioxidants

The effects of the antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin (EQ), and sodium L-ascorbate (SA) on two stage chemical carcinogenesis were investigated in male F344 rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-ethyl-N-hydroxyethylnitrosamine (EHEN), N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) or N-methylnitrosourea (MNU). BHA was given in diet at a dose level of 0.5 or 2.0%, BHT at 1.0%, SA at 5.0% and EQ at 0.8% for 29-51 weeks. Complete autopsy was performed at sacrifice and organs were examined histologically for the presence of preneoplastic and neoplastic lesions. All of the antioxidants tested exerted a positive influence on the development of BBN- or MNU-initiated bladder carcinogenesis. Similarly, these chemicals tended to enhance the appearance of forestomach tumors although the data gained after BHT administration were not significant. In clear contrast, no effect was observed on glandular stomach carcinogenesis and, with the exception of SA, the antioxidants all showed inhibition of the development of preneoplastic and neoplastic lesions in the liver. EQ increased the occurrence of renal adenoma in EHEN-treated rats. Clear differences were observed with respect to the modification of thyroid carcinogenesis after MNU initiation, BHT demonstrating strong promotion activity whereas BHA and SA had no effect. Thus organ specificity, with regard to both direction of modification and to the effects of individual antioxidants was apparent, this intriguing finding offering hope for the development of future experimental approaches for elucidation of the mechanisms underlying chemical carcinogenesis.