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Metabolic activation of nitroarenes for their mutagenicity in Salmonella typhimurium TA98
89 of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770 (Japan) Studies on mutagenicity-augmenting factors in soy sauce
We have previously reported that soy sauce from which tyramine and other mutagen precursors were removed by treatment with charcoal contained a factor which increased 9-fold the mutagenicity of nitrite-treated tyramine. Mutation of Salmonella typhimurium strain TA100 was assayed by the procedure of Maron and Ames with the modification of preincubation (at 37 ° C for 20 min) in the absence and presence of $9 mix. The charcoal-treated soy sauce (CSS) had no effect when its mutagenicity was assayed without preincubation. The CSS augmented the mutagenicity of nitrite-treated bamethan analogues (etilefrine, phenylephrjne and synephrine) and tyramine analogues ( p-coumaric acid, p-hydroxyphenyl pyruvic acid and p-hydroxyphenetyl alcohol) from severalto more than 10-fold. However, it had little effect on the mutagenicity of 4-nitroquinoline 1-oxide, benzo[a]pyrene, 2-aminoanthracene and several other well-known mutagens. The mutagenicityaugmenting factors in the CSS seemed to be sugars because they were stable to light irradiation and heat at 100°C for 10 rain. Fractionation of the CSS by HPLC revealed that several fractions had the mutagenicity-augmenting activity for nitritetreated tyramine. When 16 sugars expected to be eluted in these fractions were examined for the mutagenicity-augmenting activity, glucose, mannose and glycerol showed weak activity and therefore they accounted for a part of the mutagenicityaugmenting activity in the CSS.
15 Hirayama, T., K. Iguchi and T. Watanabe, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607 (Japan) Metabolic activation of nitroarenes for their mutagenicity in Salmonella typhimurium TA98
In order to elucidate the mechanisms of mutagenic activation of nitroarenes, we tested the mutagenic potency of 18 kinds of nitroarenes including nitrated biphenyl, fluorene, phenanthrene
and pyrene on Salmonella typhimurium TA98 in the absence and presence of $9 mix. The mutagenicity of 2,4-dinitrobiphenyl derivatives together with 4-nitrobiphenyl was enhanced by the addition of $9 mix. 2,4,6-Trinitrobiphenyl (3 net rev./10 ~tg without $9) was activated 60-fold by the mammalian metabolic activation system (181 net rev./10/xg in 10% $9). The mutagenic potency of 2,4,2',4'-tetranitrobiphenyl in TA98, TA98NR and TA98/1,8-DNP 6 was also enhanced by the addition of 10% $9. But 1-nitropyrene and 1,3-dinitropyrene, which are well-known mutagens, were deactivated to 3% and 0.4%, respectively, by the addition of 10% $9. Separate addition of microsomal and cytosolic fractions slightly activated the mutagenicity of 2,4,6-trinitrobiphenyl, and 2,4,2',4'-tetranitrobiphenyl was activated not only by $9 but also by cytosolic fraction. Further, the structures of the mutagenic metabolites of 2,4,2',4'-tetranitrobiphenyl by $9 mix were investigated. 2,4,2',4'-Tetranitrobiphenyl (80 mg, 193 net rev./0.1/~g in 10% $9) was incubated with $9 mix (40 ml) at 37 °C for 48 h, and the mixture was extracted with ethyl acetate. SiO2 and A1203 chromatographic separations were performed and 2,4-diamino-2',4'-dinitrobiphenyl (10 mg, 4646 net rev./0.05 /~g without $9) was isolated as the direct-acting mutagenic metabolite.
16 Hirose, M., K. Takayama, K. Wakabayashi, T. Sugimura and M. Nagao, Carcinogenesis Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104 (Japan) Formation of D N A adduct by MelQx: relation between administration dose and adduct level
A mutagenic and carcinogenic 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is present in cooked food. When MeIQx was given orally to rats at concentrations of 0.4-400 ppm for 12 weeks, the DNA adduct levels in the liver increased, depending on the concentration of MeIQx and feeding times. In this study, male F344 rats were administered MeIQx at concentrations of 0.1, 0.4, 8 and 400 ppm in the diet for 16 weeks, and the DNA adducts in the liver, pancreas and colon were
We have previously reported that soy sauce from which tyramine and other mutagen precursors were removed by treatment with charcoal contained a factor which increased 9-fold the mutagenicity of nitrite-treated tyramine. Mutation of Salmonella typhimurium strain TA100 was assayed by the procedure of Maron and Ames with the modification of preincubation (at 37 ° C for 20 min) in the absence and presence of $9 mix. The charcoal-treated soy sauce (CSS) had no effect when its mutagenicity was assayed without preincubation. The CSS augmented the mutagenicity of nitrite-treated bamethan analogues (etilefrine, phenylephrjne and synephrine) and tyramine analogues ( p-coumaric acid, p-hydroxyphenyl pyruvic acid and p-hydroxyphenetyl alcohol) from severalto more than 10-fold. However, it had little effect on the mutagenicity of 4-nitroquinoline 1-oxide, benzo[a]pyrene, 2-aminoanthracene and several other well-known mutagens. The mutagenicityaugmenting factors in the CSS seemed to be sugars because they were stable to light irradiation and heat at 100°C for 10 rain. Fractionation of the CSS by HPLC revealed that several fractions had the mutagenicity-augmenting activity for nitritetreated tyramine. When 16 sugars expected to be eluted in these fractions were examined for the mutagenicity-augmenting activity, glucose, mannose and glycerol showed weak activity and therefore they accounted for a part of the mutagenicityaugmenting activity in the CSS.
15 Hirayama, T., K. Iguchi and T. Watanabe, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607 (Japan) Metabolic activation of nitroarenes for their mutagenicity in Salmonella typhimurium TA98
In order to elucidate the mechanisms of mutagenic activation of nitroarenes, we tested the mutagenic potency of 18 kinds of nitroarenes including nitrated biphenyl, fluorene, phenanthrene
and pyrene on Salmonella typhimurium TA98 in the absence and presence of $9 mix. The mutagenicity of 2,4-dinitrobiphenyl derivatives together with 4-nitrobiphenyl was enhanced by the addition of $9 mix. 2,4,6-Trinitrobiphenyl (3 net rev./10 ~tg without $9) was activated 60-fold by the mammalian metabolic activation system (181 net rev./10/xg in 10% $9). The mutagenic potency of 2,4,2',4'-tetranitrobiphenyl in TA98, TA98NR and TA98/1,8-DNP 6 was also enhanced by the addition of 10% $9. But 1-nitropyrene and 1,3-dinitropyrene, which are well-known mutagens, were deactivated to 3% and 0.4%, respectively, by the addition of 10% $9. Separate addition of microsomal and cytosolic fractions slightly activated the mutagenicity of 2,4,6-trinitrobiphenyl, and 2,4,2',4'-tetranitrobiphenyl was activated not only by $9 but also by cytosolic fraction. Further, the structures of the mutagenic metabolites of 2,4,2',4'-tetranitrobiphenyl by $9 mix were investigated. 2,4,2',4'-Tetranitrobiphenyl (80 mg, 193 net rev./0.1/~g in 10% $9) was incubated with $9 mix (40 ml) at 37 °C for 48 h, and the mixture was extracted with ethyl acetate. SiO2 and A1203 chromatographic separations were performed and 2,4-diamino-2',4'-dinitrobiphenyl (10 mg, 4646 net rev./0.05 /~g without $9) was isolated as the direct-acting mutagenic metabolite.
16 Hirose, M., K. Takayama, K. Wakabayashi, T. Sugimura and M. Nagao, Carcinogenesis Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104 (Japan) Formation of D N A adduct by MelQx: relation between administration dose and adduct level
A mutagenic and carcinogenic 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is present in cooked food. When MeIQx was given orally to rats at concentrations of 0.4-400 ppm for 12 weeks, the DNA adduct levels in the liver increased, depending on the concentration of MeIQx and feeding times. In this study, male F344 rats were administered MeIQx at concentrations of 0.1, 0.4, 8 and 400 ppm in the diet for 16 weeks, and the DNA adducts in the liver, pancreas and colon were