Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells
Effect of chrysin, a flavonoid compound, on the mutagenic activity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and benzo(a)pyrene (B(a)P) in bacterial and human hepatoma (HepG2) cells
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DOI：
10.1007/s00204-003-0469-4
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发表时间：
2003-01-01
影响因子：
6.1
通讯作者：
Knasmüller, S
中科院分区：
文献类型：
--
作者：
Uhl, M;Ecker, S;Knasmüller, S
本研究的目的是探讨白杨素（CR），一种黄酮类化合物，包含在许多水果，蔬菜和蜂蜜的抗突变作用。早期的细菌指示剂研究表明，CR是黄酮类化合物中最有效的抗突变剂之一。在本研究中，我们测试了沙门氏菌菌株TA 98和TA 100中的化合物与苯并（a）芘（B（a）P）和2-氨基-1-甲基-6-苯基咪唑[4，5-B]吡啶（PhIP）的组合，发现在10至100 μ g/ml的浓度范围内具有显著的保护活性。在所有检测浓度下，化合物本身均无致突变活性。在人源性HepG 2细胞的微核（MN）试验中，观察到不同的活性模式。CR本身在剂量水平大于或等于15 μ g/ml时引起MN的显著诱导;在与B（a）P和PhIP的联合实验中，获得U形剂量-反应曲线，并且仅在窄剂量范围（5-10 μ g/ml）内发现保护作用。我们的研究结果表明，CR在细菌细胞中的抗突变作用的分子机制与HepG 2细胞中的作用不同。早期报道表明，CR对细菌指示剂中的B（a）P和杂环胺的抗突变作用是由于抑制CYP 1A的活性。与此相反，我们发现CR在HepG 2细胞中显著诱导CYP 1A 1活性。还可以排除的是，参与多环芳烃解毒的GST的诱导解释了CR对B（a）P的保护作用，因为这种酶在HepG 2细胞中没有被显著诱导。在PhIP的情况下，暴露于CR后在人源性HepG 2细胞中观察到的UDGPT诱导和/或磺基转移酶抑制可能在抗突变作用中发挥作用。总之，我们的研究结果表明，使用细菌指示剂的抗突变性研究数据不能外推至HepG 2细胞，CR在后者细胞中以较高剂量水平引起遗传毒性效应。这些意见对人类的化学预防策略的影响进行了讨论。
The aim of the present study was to investigate the antimutagenic effects of chrysin (CR), a flavonoid compound contained in many fruits, vegetables and honey. Earlier investigations with bacterial indicators showed that CR is one of the most potent antimutagens among the flavonoids. In the present study, we tested the compound in the Salmonella strains TA98 and TA100 in combination with benzo(a)pyrene (B(a)P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and found pronounced protective activity over a concentration range between 10 and 100 mug/ml. The compound itself was devoid of mutagenic activity at all concentrations tested. In the micronucleus (MN) assay with human-derived HepG2 cells, a different pattern of activity was seen. CR itself caused significant induction of MN at dose levels greater than or equal to15 mug/ml; in combination experiments with B(a)P and PhIP, U-shaped dose-response curves were obtained and protection was found only in a narrow dose range (5-10 mug/ml). Our findings indicate that the molecular mechanisms that account for the antimutagenic effects of CR in bacterial cells are different from those responsible for the effects in HepG2 cells. Earlier reports indicate that the antimutagenic effects of CR towards B(a)P and heterocyclic amines in bacterial indicators is due to inhibition of the activity of CYP1A. In contrast to this, we found a significant induction of CYP1A1 activity in HepG2 cells by CR. It can also be excluded that induction of GST, which is involved in the detoxification of polycyclic aromatic hydrocarbons accounts for the protective effects of CR against B(a)P since this enzyme was not significantly induced in the HepG2 cells. In the case of PhIP, induction of UDGPT and/or inhibition of sulfotransferase seen in human derived HepG2 cells after exposure to CR might play a role in the antimutagenic effects. In conclusion, our findings show that data from antimutagenicity studies with bacterial indicators cannot be extrapolated to HepG2 cells, and that CR causes genotoxic effects at higher dose levels in the latter cells. The implications of these observations for human chemoprevention strategies are discussed.