Chemoprevention of heterocyclic amine-induced carcinogenesis by phenolic compounds in rats

Chemopreventive effects of synthetic and naturally occurring antioxidants o n heterocyclic amine (HCA)-induced rat carcinogenesis and mechanisms of inh ibition were assessed. In a medium-term liver bioassay, combined treatment with 0.03% 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and synthe tic antioxidants such as 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), BHA, BHT, tert-butylhydroquinone (TBHQ) and propyl gallate, each at a dose of 0 .25%, and troglitazone at doses 0.5 and 0.1%, potently inhibited developmen t of glutathione S-transferase placental form (GST-P) positive foci as comp ared with MeIQx alone values. Of these antioxidants, HTHQ showed the greate st activity. Green tea catechins tended to inhibit GST-P positive foci deve lopment, while quercetin, rutin, curcumin, daidzin, ferulic acid and genist in all exerted significant enhancing effects. HTHQ also inhibited 2-amino-1 -methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colon carcinogenesis in a two stage colon carcinogenesis model using 1,2-dimethylhydrazine (DMH) as an initiator. Immunohistochemically detected PhIP-DNA adduct positive n uclei in the colon induced by continuous oral treatment with 0.02% PhIP for 2 weeks decreased by the combined treatment with 0.5 or 0.125% HTHQ. Metho xyresorfin O-demethylase activity in rat liver microsomes in vitro was clea rly inhibited by the addition of HTHQ, BHA, BHT, TBHQ or propyl gallate, wi th particularly strong inhibition being observed in HTHQ. However, the CYP1 A2 level in rat liver increased after oral treatment with HTHQ for 2 weeks. These results indicate that synthetic antioxidants, HTHQ in particular, is a very strong chemopreventor of HCA-induced carcinogenesis. It is suggeste d that depression of metabolic activation rather than antioxidant activity is responsible for the observed effect. However, other mechanisms, includin g the effects on phase II enzymes cannot be ruled out. (C) 1999 Elsevier Sc ience Ireland Ltd. All rights reserved.