Structure-Dependent Modulation of Aryl Hydrocarbon Receptor-Mediated Activities by Flavonoids
Structure-Dependent Modulation of Aryl Hydrocarbon Receptor-Mediated Activities by Flavonoids
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DOI：
10.1093/toxsci/kfy075
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发表时间：
2018-07-01
影响因子：
3.8
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
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作者：
Jin, Un-Ho;Park, Hyejin;Safe, Stephen
膳食类黄酮用于治疗多种疾病，其在肠道中的抑制作用部分是由于与肠道微生物菌群的相互作用，并可能是由于调节芳烃受体（AhR）信号传导。在这项研究中，我们研究了14种黄酮类化合物在Caco 2结肠癌细胞中的结构依赖性AhR活性，以诱导CYP 1A 1和UGT 1A 1基因表达为终点。AhR活化的主要结构决定因素是羟基的数量，其中五羟基类黄酮（桑色素除外）>六羟基类黄酮>四羟基/三羟基类黄酮，并且后一种化合物中的一些如芹菜素表现出诱导CYP 1A 1的AhR拮抗剂活性。模拟表明，虽然槲皮素和芹菜素主要与相同的残基相互作用，但与CYP 1A 1拮抗剂芹菜素相比，特定AhR残基与CYP 1A 1激动剂槲皮素之间的相互作用强度不同;因此，这种相互作用可能表明调节CYP 1A 1活性的潜在开关。羟基类黄酮对UGT 1A 1诱导的结构依赖性效应与诱导CYP 1A 1所观察到的相似，除了毛地黄黄酮和芹菜素诱导的UGT 1A 1水平与TCDD所观察到的相似，而这两种化合物均为CYP 1A 1的AhR拮抗剂。因此，在Caco 2细胞中的类黄酮对Ah-responsibility和与丁酸盐的相互作用的影响是配体结构和响应依赖性的，这些活动是一致的羟基类黄酮作为选择性AhR调节剂。
Dietary flavonoids are used in treatment of multiple diseases, and their antiinflammatory effects in the intestine are due, in part, to interactions with gut microflora and possibly due to modulation of aryl hydrocarbon receptor (AhR) signaling. In this study, we investigated the structure-dependent AhR activity of 14 flavonoids in Caco2 colon cancer cells using induction of CYP1A1 and UGT1A1 gene expression as endpoints. A major structural determinant for AhR activation was the number of hydroxyl groups where pentahydroxyflavonoids (with the exception of morin)> hexahydroxyflavonoids> tetra-/trihydroxyflavonoids, and some of the latter compounds such as apigenin exhibited AhR antagonist activity for induction of CYP1A1. Simulations suggest that while quercetin and apigenin interact primarily with the same residues, the strength of interactions between specific AhR residues with CYP1A1 agonist, quercetin, in comparison with CYP1A1 antagonist, apigenin, is different; thus, such interactions are presumably indicative of potential switches for modulating CYP1A1 activity. The structure-dependent effects of the hydroxyl flavonoids on induction of UGT1A1 were similar to that observed for induction of CYP1A1 except that luteolin and apigenin induced UGT1A1 levels similar to that observed for TCDD, whereas both compounds were AhR antagonists for CYP1A1. Thus, the effects of the flavonoids in Caco2 cells on Ah-responsiveness and interactions with butyrate were both ligand structure-and response-dependent and these activities are consistent with hydroxyflavonoids being selective AhR modulators.