Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.
Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.
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DOI：
10.1371/journal.pone.0074917
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Haarmann-Stemmann T
中科院分区：
文献类型：
--
作者：
Vrzal R;Frauenstein K;Proksch P;Abel J;Dvorak Z;Haarmann-Stemmann T
Khellin 和 visnagin 是两种呋喃色酮，经常出现在亚洲和中东的民族医学配方中。这两种化合物都具有抗炎和镇痛特性，因此现代医学使用这些化合物或结构相关的衍生物来治疗白癜风、支气管哮喘和肾绞痛。尽管经常使用，但维斯纳金和凯林的潜在毒性迄今为止尚未得到很好的表征。许多天然化合物可调节细胞色素 P450 1A1 (CYP1A1) 的表达和活性，众所周知，细胞色素 P450 1A1 可以生物激活促致癌物。该酶的表达受芳基烃受体 (AHR) 控制，AHR 是一种配体激活的转录因子和药物代谢调节剂。在这里，我们研究了两种呋喃色酮对人 HepG2 肝癌细胞和原代人肝细胞中 AHR 信号传导的影响。两种化合物均以剂量依赖性方式反式激活异生素反应元件 (XRE) 驱动的报告基因活性，并诱导 HepG2 细胞和原代肝细胞中的 CYP1A1 转录。后者在特定 AHR 拮抗剂存在下被废除。在 HepG2 细胞和原代肝细胞中进行的 CYP1A 酶活性测定揭示了两种呋喃色酮对酶活性的抑制，这可能与异生物质和共同给药的治疗药物的代谢相关。观察到的 AHR 基因组其他几个成员的诱导，其基因产物参与细胞生长、分化和迁移的调节，表明迫切需要对 visnagin 和 khelllin 进行进一步的毒理学表征，以尽量减少潜在的药物相互作用和在这些呋喃色酮治疗使用过程中可能发生的其他毒副作用。
Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1), which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE)-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.
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DOI：
10.1016/0165-1218(95)90070-5
发表时间：
1995-11-01
期刊：
MUTATION RESEARCH-GENETIC TOXICOLOGY
影响因子：
--
作者：
EDENHARDER, R;SPETH, C;PLATT, KL
通讯作者：
PLATT, KL
影响因子：
10.4
作者：
Fabricant, DS;Farnsworth, NR
通讯作者：
Farnsworth, NR
DOI：
10.1073/pnas.0701764104
发表时间：
2007-05-22
影响因子：
11.1
作者：
Fritsche, Ellen;Schaefer, Claudia;Krutmann, Jean
通讯作者：
Krutmann, Jean
影响因子：
13.6
作者：
Chao, How-Ran;Wang, Ya-Fen;Tsou, Tsui-Chun
通讯作者：
Tsou, Tsui-Chun
影响因子：
4.8
作者：
Baba, T;Mimura, J;Fujii-Kuriyama, Y
通讯作者：
Fujii-Kuriyama, Y