Antimutagenic effects and possible mechanisms of action of vitamins and related compounds against genotoxic heterocyclic amines from cooked food

Possible antimutagenic activity of 26 vitamins and related compounds - asco rbic acid, beta-carotene, cyanocobalamin, folic acid, nicotinic acid, nicot inamide, pantothenic acid, pyridoxale, pyridoxamine, pyridoxine, retinal, r etinol, retinoic acid, retinyl acetate, retinyl palmitate, riboflavin, ribo flavin 5'-phosphate, flavin adenine dinucleotide (FAD), a-tocopherol, alpha -tocopherol acetate, vitamins K-1, K-3, K-4, 1,4-naphthoquinone, and coenzy me Q(10) - was tested against six heterocyclic amine (HCA) mutagens, i.e., 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-3,4-dimethyl-imidazo l[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (M eIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-6-me thyl-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 3-amino-1-methyl-5H-pyr ido[4,3-b]indole (Trp-P-2) in the Salmonella/reversion assay using tester s trains Salmonella typhimurium TA 98 and TA 100. Retinol, retinal, riboflavi n, riboflavin 5'-phosphate, FAD, vitamins K-1, K-3, K-4, 1,4-naphthoquinone , and coenzyme Q(10) caused a concentration-dependent decrease in the mutag enicity of all six mutagens in both tester strains. Quantification of antim utagenic potencies by calculating ID50 values (inhibitory dose for 50% redu ction of mutagenic activity) from dose-response curves resulted in the foll owing data (nmol/plate): retinol: 480-1400; retinal: 268-441; riboflavin: 2 5- > 100; riboflavin 5'-phosphate: 800-4723; FAD: 970- > 1000; vitamin K-1: 401-740; vitamin K-3 (menadione): 85-590; vitamin K-4: 45-313; 1,4-naphtho quinone: 170-290; coenzyme Q(10): 490-860. In general, there were no major differences between HCAs tested except in part with Trp-P-2 nor between the two tester strains. In enzyme kinetic experiments with Salmonella, retinol , vitamins K-3, and K-4 behaved as competitive inhibitors of IQ induced mut agenesis. However, at the highest concentration of menadione (200 nmol/plat e) and of riboflavin 5'-phosphate (2000 nmol/plate), non-competitive inhibi tion was observed. At other concentrations of riboflavin 5'-phosphate and a t all concentrations of FAD, meaningful interpretation of enzyme kinetics w ere not possible. Reduction of the activity of 7-ethoxy- and 7-methoxyresor ufin-O-dealkylases with IC50 values of 2.03-30.8 mu M indicated strong inhi bition of 1A1 and 1A2 dependent monooxygenases by menadione and retinol. Ri boflavin 5'-phosphate and FAD were less effective (IC50: 110-803.7 mu M). N icotinamide-adenine-dinucleotidephosphate (NADPH) cytochrome P-450 reductas e was not affected by retinoids but stimulated by naphthoquinones and both riboflavin derivatives up to about 50 and 80%, respectively. Again, the mut agenic activity of N-hydroxy-2-amino-3-methyl-imidazo[4,5-f]quinoline (N-OH -IQ) in Salmonella was not suppressed by K-vitamins but marginally reduced by retinol, retinal, and FAD but distinctly by riboflavin 5'-phosphate. in various experiments designed for modulation of the mutagenic response, inhi bition of metabolic activation of IQ to N-OH-IQ was found to be the only re levant mechanism of antimutagenesis of menadione while a weak contribution of an other way seemed possible for retinol and FAD. (C) 1999 Elsevier Scie nce B.V. All rights reserved.