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首页> 外文期刊>Mutation research. Genetic toxicology testing >INHIBITION OF MUTAGENESIS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) BY COUMARINS AND FURANOCOUMARINS, CHROMANONES AND FURANOCHROMANONES
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INHIBITION OF MUTAGENESIS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) BY COUMARINS AND FURANOCOUMARINS, CHROMANONES AND FURANOCHROMANONES

机译：香豆素和呋喃香豆素，色氨酸和呋喃色酮抑制2-氨基-3-甲基咪唑并[4,5-F]喹啉（IQ）诱变

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A total of 51 natural and synthetic simple coumarins, furanocoumarins, chromanones, furanochromanones and some structurally related compounds were tested for their antimutagenic potencies with respect to IQ in Salmonella typhimurium TA 98. Antimutagenic potencies were quantified by the inhibitory dose for 50% reduction of mutagenic activity (ID50) and by the remaining mutagenic activity at the highest dose tested. Antimutagenic activities of the parent compounds were weak (ID50: 500-750 nmol/plate) but increased in the coumarin series with introduction of hydroxy, methoxy and (or) methyl groups at carbons 4, 5, 6 and 7 (ID50: 70-400 nmol/plate). However, the antimutagenicity of compounds with hydroxy or methoxy substituents at C-5, C-6 and C-7 all together was low. Moreover, a hydroxy or methoxy function at C-8 greatly reduced antimutagenic potency. This was in part also true for substituents at C-3. Coumarin glycosides and glucuronides of antimutagenic aglycones were, however, inactive. Introduction of a carboxyl function rendered the respective coumarin inactive. Surprisingly, some synthetic coumarins with a bromo or iodo substituent at C-8 or a benzyloxy function at C-5 were found to be very potent antimutagens (ID50: 9.3-14.5 nmol/plate), whereas analogues possessing a bromo or formyl function at C-5 were less effective (ID50: 176 and 395 nmol/plate). Furanocoumarins and furanochromanones were very potent antimutagens (ID50: 5.1-26.5 nmol/plate). In enzyme kinetic experiments with Salmonella the inhibition mechanisms of xanthotoxin and visnagin were concentration dependent, being non-competitive at low concentrations. Reduction of the activity of 7-ethoxy- and 7-methoxyresorufin-O-dealkylases with IC50 values of 1.2-11.7 mu M indicated strong inhibition of cytochrome P-450 1A1 and 1A2 dependent monooxygenases by some of the furanocoumarines and -chromanones. The mutagenic activity of N-hydroxy-IQ in Salmonella, however, was not reduced by any of these compounds. In various experiments designed for modulation of the mutagenic response inhibition of activation of IQ to N-OH-IQ was found to be the only relevant mechanism of antimutagenesis of psoralen, angelicin and khellin.
机译：在鼠伤寒沙门氏菌TA 98中测试了总共51种天然和合成的简单香豆素，呋喃香豆素，发色酮，呋喃色酮和一些与结构相关的化合物对IQ的抗诱变能力。通过抑制剂量降低诱变50％量化了抗诱变能力。活性（ID50）和在最高测试剂量下的剩余诱变活性。母体化合物的抗诱变活性较弱（ID50：500-750 nmol /板），但在香豆素系列中却增加了，因为在碳4、5、6和7上引入了羟基，甲氧基和（或）甲基（ID50：70- 400 nmol /板）。然而，在C-5，C-6和C-7处一起具有羟基或甲氧基取代基的化合物的抗诱变性均很低。此外，C-8的羟基或甲氧基功能大大降低了抗诱变能力。对于C-3处的取代基也部分如此。然而，抗诱变糖苷配基的香豆素苷和葡糖醛酸苷没有活性。羧基功能的引入使各自的香豆素失去活性。令人惊讶地，发现一些在C-8具有溴或碘取代基或在C-5具有苄氧基功能的合成香豆素是非常有效的抗突变蛋白（ID50：9.3-14.5nmol /板），而在C-8具有溴或甲酰基功能的类似物。 C-5效果较差（ID50：176和395 nmol /板）。呋喃香豆素和呋喃并二氢呋喃酮是非常有效的抗突变蛋白（ID50：5.1-26.5 nmol /板）。在用沙门氏菌进行的酶动力学实验中，黄嘌呤毒素和visnagin的抑制机制是浓度依赖性的，在低浓度下是非竞争性的。 IC50值为1.2-11.7μM的7-乙氧基-和7-甲氧基-异鲁柔宁-O-脱烷基酶的活性降低表明某些呋喃香豆素和-苯并二氢呋喃酮对细胞色素P-450 1A1和1A2依赖性单加氧酶有很强的抑制作用。然而，沙门氏菌中N-羟基-IQ的诱变活性并未因任何这些化合物而降低。在为调节诱变响应而设计的各种实验中，发现智商对N-OH-IQ的激活抑制是补骨脂素，当归素和凯勒琳抗突变的唯一相关机制。

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