STRONG ANTIMUTAGENIC ACTIVITY OF THE NOVEL LIPOPHILIC ANTIOXIDANT 1-O-HEXYL-2,3,5-TRIMETHYLHYDROQUINONE AGAINST HETEROCYCLIC AMINE-INDUCED MUTAGENESIS IN THE AMES ASSAY AND ITS EFFECT ON METABOLIC-ACTIVATION OF 2-AMINO-6-METHYLDIPYRIDO[1,2-A-3',2'-D]IMIDAZOLE (GLU-P-1)

Antimutagenic effects of a novel lipophilic antioxidant, 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), and other known antioxidants against heterocyclic amine- or other mutagen-induced mutagenesis were examined in the Ames assay using Salmonella strain TA 98 to access the chemopreventive effects of antioxidants on heterocyclic amine-induced carcinogenesis, Further the mechanisms of inhibition by HTHQ were accessed, HTHQ was shown to potently inhibit mutagenesis induced by all of 8 different heterocyclic amines at rates between 100% and 63% in the presence of S9 mix, When the protection of HTHQ against 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1)-induced mutagenesis was compared with known antioxidants t-butylhydroquinone, propyl gallate, BHA, BHT and alpha-tocopherol, HTHQ showed the greatest effect, Among hexyl, butyl, ethyl and methyl derivatives of 1-O-alkyl-2,3,5-trimethylhydroquinone, HTHQ was the most effective in inhibiting Glu-P-1-, 3-amino-1-methyl-5-H-pyrido[4,3-b]indole (Trp-P-2)- or 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced mutagenesis, On the other hand, HTHQ did not inhibit mutagenic activity induced by other mutagens such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamid (AF-2) and benzo[a]pyrene. HTHQ weakly inhibited that due to direct mutagen 2-nitro derivative of 2-amino-3,8-dimethylimidazo[4,5-]quinoxaline (MeIQx) only in the presence of S9 mix, No such influence on a 2-nitro derivative of 2-amino-3,4-dimethylimidazo[4,5-f]quinol (MeIQ) or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced mutagenesis, was observed with or without the S9 mix, HTHQ slightly inhibited mutagenesis induced by activated Glu-P-1, a direct acting proximate metabolite of Glu-P-1, in the absence of the so mix, HPLC analysis revealed activated Glu-P-1 to be formed by incubating Glu-P-1 with the S9 mix, but this was considerably decreased by the addition of HTHQ. These results indicate that HTHQ is a powerful antimutagenic compound and specifically acts against heterocyclic amines, Its antimutagenic activity appeared to exert by both inhibiting metabolic activation of heterocyclic amines and action on activated N-hydroxy species,