Phenolic antioxidants and the inhibition of hepatotoxicity from n-dimethylnitrosamine formed in situ in the rat stomach

Abstract

The effect of the widely used edible stabilizers propyl gallate (PG), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ) on intragastric N-nitrosamine formation was studied. Rats were given by gastric intubation, sodium nitrite (125 mg/kg) and dimethylamine (1000 mg/kg) followed immediately by the test compound in doses of 25, 75 or 225 mg/kg. Ascorbate (200 mg/kg) was used as a positive control. Indices of N-nitrosamine formation 48 hr after dosing were the activities of serum glutamic-oxalacetic transaminase (GOT) glutamic-pyruvic transaminase (GPT), and ornithine-carbamoyl transferase (OCT), and the extent of hepatic necrosis. The nitrosamine-forming mixture alone produced extensive hepatic necrosis and 24-, 19- and 4-fold increases in serum GOT, GPT and OCT activities respectively. Enzyme induction was completely suppressed by ascorbate. PG completely protected against hepatic necrosis and enzyme induction at 225 mg/kg, and to a lesser extent at 75 mg/kg. TBHQ gave 60% protection against necrosis and appreciably suppressed enzyme activity increases at 225 mg/kg. BHA and BHT at all dose levels, PG at 25 mg/kg and TBHQ at 25 and 75 mg/kg neither demonstrated protective activity nor induced any lethality. Hence at approximately equimolar levels of nitrite and antioxidant, PG and TBHQ exerted an inhibitory effect on nitrosamine formation, but at lower levels all four antioxidants tested had no observable effect on the nitrosamine-forming system.