Suppression of Diethylnitrosamine‐initiated Preneoplastic Foci Development in the Rat Liver by Combined Administration of Four Antioxidants at Low Doses

Potential synergism between 4 antioxidants acting at low doses on development of glutathione S‐transferase placental form (GST‐P)‐positive liver cell foci was examined in male rats initially given diethylnitrosamine (200 mg/kg, i.p.). Beginning 2 weeks after the initiation, rats received the antioxidants, individually or in combination, in the diet for 6 weeks. All rats were subjected to two‐thirds partial hepatectomy at week 3 and killed at week 8. The numbers and areas of GST‐P‐positive foci were significantly decreased by single treatment with butylated hydroxyanisole (BHA, 1%), tert‐butylhydroquinone (TBHQ, 1%) and catechol (0.8%), but not with sesamol (0.5%). Combined treatments (BHA+TBHQ, catechol + sesamol, or all 4 chemicals) at a quarter of the above dose levels resulted in decrease in numbers and areas of foci to levels less than the sums of individual inhibition data obtained with the one‐quarter levels. Although these combined effects were not statistically significant in the additive model, the results indicate possible synergistic suppression of carcinogenesis by low‐dose combined treatment with anti‐cancer agents and the usefulness of the present protocol for this type of analysis.