Strong anti-mutagenic 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 chemo-preventive 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-alpha: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)acrylamide (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-f]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]quinoline (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 S9 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.
Hirose
M
M
First Department of Pathology, Nagoya City University, Medical School, Japan.
Iwata
S
S
Ito
E
E
Nihro
Y
Y
Takahashi
S
S
Mizoguchi
Y
Y
Miki
T
T
Satoh
T
T
Ito
N
N
Shirai
T
T
D000588:Amines / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D016587:Antimutagenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction; D006571:Heterocyclic Compounds / Q000493:pharmacokinetics / Q000633:toxicity; D006873:Hydroquinones / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D000588:Amines; D016588:Anticarcinogenic Agents; D016587:Antimutagenic Agents; D000975:Antioxidants; D006571:Heterocyclic Compounds; D006873:Hydroquinones; D007093:Imidazoles; D009153:Mutagens; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C081906:1-O-hexyl-2,3,5-trimethylhydroquinone; D003577:Cytochrome P-450 Enzyme System