INHIBITION OF MUTAGENESIS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) BY COUMARINS AND FURANOCOUMARINS, CHROMANONES AND FURANOCHROMANONES
INHIBITION OF MUTAGENESIS OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE (IQ) BY COUMARINS AND FURANOCOUMARINS, CHROMANONES AND FURANOCHROMANONES
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DOI：
10.1016/0165-1218(95)90070-5
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发表时间：
1995-11-01
期刊：
影响因子：
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通讯作者：
PLATT, KL
中科院分区：
文献类型：
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作者：
EDENHARDER, R;SPETH, C;PLATT, KL
共检测了51种天然和合成的简单香豆素、呋喃香豆素、色满酮、呋喃色满酮和一些结构相关的化合物在鼠伤寒沙门氏菌TA 98中对IQ的抗突变效力。通过致突变活性降低50%的抑制剂量（ID 50）和最高试验剂量下的剩余致突变活性，对抗致突变效力进行定量。母体化合物的抗突变活性较弱（ID 50：500-750 nmol/板），但在香豆素系列中，在碳4、5、6和7处引入羟基、甲氧基和（或）甲基后，抗突变活性增加（ID 50：70-400 nmol/板）。然而，在C-5、C-6和C-7处全部具有羟基或甲氧基取代基的化合物的抗突变性低。此外，C-8位的羟基或甲氧基官能团大大降低了抗突变效力。这在一定程度上也适用于C-3位的取代基。香豆素苷和葡萄糖醛酸苷的抗突变苷元，但是，无活性。羧基官能团的引入使相应的香豆素失活。令人惊讶的是，发现一些在C-8处具有溴或碘取代基或在C-5处具有苄氧基官能团的合成香豆素是非常有效的抗突变剂（ID 50：9.3-14.5 nmol/板），而在C-5处具有溴或甲酰基官能团的类似物效果较差（ID 50：176和395 nmol/板）。呋喃香豆素和呋喃色满酮是非常有效的抗突变剂（ID 50：5.1-26.5 nmol/板）。在沙门氏菌的酶动力学实验中，黄毒素和visnagin的抑制机制是浓度依赖性的，在低浓度下是非竞争性的。7-乙氧基-和7-甲氧基试卤灵-O-脱烷基酶的活性降低，IC 50值为1.2-11.7 μ M，表明某些呋喃香豆素和-色满酮强烈抑制细胞色素P-450 1A 1和1A 2依赖性单加氧酶。然而，这些化合物中的任何一种都没有降低沙门氏菌中N-羟基-IQ的致突变活性。在设计用于调节致突变反应的各种实验中，发现抑制IQ对N-OH-IQ的激活是pesticen、angelicin和khellin抗突变的唯一相关机制。
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.