Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish
Accumulation and metabolism of the anticancer flavonoid 5,7-dimethoxyflavone compared to its unmethylated analog chrysin in the Atlantic killifish
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DOI：
10.1016/j.cbi.2006.08.023
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发表时间：
2006-12-01
影响因子：
5.1
通讯作者：
Walle, Thomas
中科院分区：
文献类型：
--
作者：
Tsuji, Petra A.;Winn, Richard N.;Walle, Thomas
使用膳食类黄酮作为潜在的化学预防剂是一个越来越感兴趣的概念。最近的研究结果表明，甲基化黄酮具有增加代谢稳定性的优点。一种这样的化合物，天然存在的5，7-二甲氧基黄酮（5，7-DMF），已被证明是一种潜在的化学预防剂，在人类癌症起源于肝脏，口腔，食道和肺。由于生物利用度是潜在体内效应的关键问题，因此在小鱼模型（异基底）中检查了5，7-DMF及其非甲基化类似物白杨素的组织蓄积和胆汁消除。将鱼暴露于海水中的5，7-DMF、白杨素或载体对照（DMSO <0.01%）8 h。在5 μ M暴露水平下未观察到毒性。收获组织和胆汁，并通过HPLC和LC/MS进行分析，以定量和鉴别母体化合物和代谢产物。5，7-DMF在检查的所有组织中蓄积20倍至100倍，在肝脏和脑中蓄积最高，而白杨素在除肝脏外的任何组织中几乎检测不到。暴露于白杨素的鱼的胆汁中含有非常低浓度的不变白杨素，但高浓度的两个葡萄糖醛酸结合物。在暴露于5，7-DMF的鱼的胆汁中，可检测到大量的母体化合物以及O-脱甲基5，7-DMF的葡萄糖醛酸缀合物。总之，我们的研究表明，与白杨素相比，5，7-DMF在体内具有较高的组织蓄积和有限的代谢，使这种黄酮成为一种有前途的化学预防分子。(c)2006年由Elsevier爱尔兰有限公司出版。
The use of dietary flavonoids as potential chemopreventive agents is a concept of increasing interest. Recent findings indicate that methylated flavones have the advantage of increased metabolic stability. One such compound, the naturally-occurring 5,7-dimethoxyflavone (5,7-DMF), has been shown to be a potential chemopreventive agent in human cancer originating from the liver, mouth, esophagus and lung. As bioavailability is a key issue for potential in vivo effects, the tissue accumulation and biliary elimination of 5,7-DMF and its non-methylated analog chrysin were examined in a small fish model (Fundulus heteroclitus). The fish were exposed to 5,7-DMF, chrysin or vehicle control (DMSO < 0.01%) in seawater for 8 h. Toxicity was not observed at the 5 mu M exposure level. Tissues and bile were harvested and analyzed by HPLC and LC/MS for quantitation and identification of parent compound and metabolites. 5,7-DMF accumulated 20-fold to 100-fold in all tissues examined, with the highest accumulation in liver and brain, whereas chrysin was barely detectable in any tissues except the liver. The bile of chrysin-exposed fish contained very low concentrations of unchanged chrysin but high concentrations of two glucuronic acid conjugates. In the bile of 5,7-DMF-exposed fish, the parent compound was detectable in significant amounts along with glucuronic acid conjugates of O-demethylated 5,7-DMF. In conclusion, our study demonstrated high tissue accumulation and limited metabolism of 5,7-DMF compared to chrysin in vivo, making this flavone a promising chemopreventive molecule. (c) 2006 Published by Elsevier Ireland Ltd.