Botanical dietary supplements (BDS) containing hops are sold as women’s health supplements due to the potent hop phytoestrogen, 8-prenylnaringenin (8-PN), and the cytoprotective chalcone, xanthohumol. Previous studies have shown a standardized hop extract to beneficially influence chemical estrogen carcinogenesis in vitro by fostering detoxified 2-hydroxylation over genotoxic 4-hydroxylation estrogen metabolism. In this study, hop extract and its bioactive compounds were investigated for its mechanism of action within the chemical estrogen carcinogenesis pathway, which is mainly mediated through the 4-hydroxylation pathway catalyzed by CYP1B1 that can form gentoxic quinones. Aryl hydrocarbon receptor (AhR) agonists induce CYP1A1 and CYP1B1, while estrogen receptor alpha (ERα) inhibits transcription of CYP1A1, the enzyme responsible for 2-hydroxylated estrogens and the estrogen detoxification pathway. An In-Cell Western MCF-7 cell assay revealed hop extract and 6-prenylnaringenin (6-PN) degraded ERα via an AhR-dependent mechanism. Reverse transcription PCR and xenobiotic response element luciferase assays showed hop extract and 6-PN-mediated activation of AhR and induction of CYP1A1. A reduction in estrogen-mediated DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation of CYP1A1 accompanied this activity in a chromatin immunoprecipitation assay. Ultimately, hop extract and 6-PN induced preferential metabolism of estrogens to their detoxified form in vitro. These results suggest that the standardized hop extract and 6-PN activate AhR to attenuate epigenetic inhibition of CYP1A1 through degradation of ERα, ultimately increasing 2-hydroxylated estrogens. A new mechanism of action rationalizes the positive influence of hop BDS and 6-PN on oxidative estrogen metabolism in vitro and, thus, potentially on chemical estrogen carcinogenesis. The findings underscore the importance of elucidating various biological mechanisms of action and standardizing BDS to multiple phytoconstituents for optimal resilience promoting properties.

中文翻译：

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啤酒花中的 6-异戊二烯基柚皮素破坏 ERα 介导的 CYP1A1 下调以促进雌激素解毒

由于有效的啤酒花植物雌激素 8-异戊二烯基柚皮素 (8-PN) 和细胞保护性查耳酮黄腐酚，含有啤酒花的植物膳食补充剂 (BDS) 作为女性健康补充剂出售。先前的研究表明，标准化的啤酒花提取物通过促进解毒 2-羟基化而不是遗传毒性 4-羟基化雌激素代谢，从而有益地影响体外化学雌激素致癌作用。在这项研究中，研究了啤酒花提取物及其生物活性化合物在化学雌激素致癌途径中的作用机制，该途径主要通过CYP1B1催化的 4-羟基化途径介导，可形成具有毒性的醌。芳烃受体 (AhR) 激动剂诱导CYP1A1和CYP1B1，而雌激素受体α (ERα) 抑制CYP1A1 的转录，CYP1A1是负责 2-羟基化雌激素和雌激素解毒途径的酶。In-Cell Western MCF-7 细胞测定显示啤酒花提取物和 6-异戊二烯基柚皮素 (6-PN) 通过 AhR 依赖性机制降解 ERα。逆转录 PCR 和异生素反应元件荧光素酶测定显示啤酒花提取物和 6-PN 介导的 AhR 激活和CYP1A1 的诱导。在染色质免疫沉淀试验中，雌激素介导的 DNA (胞嘧啶-5)-甲基转移酶 1 (DNMT1) 下调CYP1A1 的减少伴随着这种活性。最终，啤酒花提取物和 6-PN在体外诱导雌激素优先代谢为其解毒形式. 这些结果表明，标准化啤酒花提取物和 6-PN 可激活 AhR，通过降解 ERα减弱CYP1A1 的表观遗传抑制，最终增加 2-羟基化雌激素。一种新的作用机制将啤酒花 BDS 和 6-PN 对体外氧化雌激素代谢的积极影响合理化，从而可能对化学雌激素致癌作用产生积极影响。这些发现强调了阐明各种生物作用机制和将 BDS 标准化为多种植物成分以获得最佳弹性促进特性的重要性。