Effects of ready to drink teas on AhR- and PXR-mediated expression of cytochromes P450 CYP1A1 and CYP3A4 in human cancer cell lines and primary human hepatocytes

A variety of xenobiotics are taken in the diet and they can interfere with regulatory pathways of drug metabolizing enzymes in humans. This can result in food-drug interactions, which is undesirable clinical situation where drug pharmacokinetics are influenced by dietary compounds. Xenobiotics-mediated food-drug interactions include the induction of drug metabolizing cytochromes P450. The expression of the most important inducible cytochromes CYP1A and CYP3A4 are regulated by xenoreceptors PXR and AhR.We examined extracts from 17 different flavoured ready to drink teas (RDTs) for their capabilities to activate PXR and AhR receptors and to induce CYP3A4 and CYP1A genes. Primary cultures of human hepatocytes and cancer cell lines HepG2 and LS174T were used as in vitro models. Gene reporter assays, RT-PCR and Western blots were performed.We identified three RDTs that induced CYP3A4 mRNA and protein, implying a potential for food-drug interactions. Several RDTs slightly elevated CYP1A1 expression or activated AhR.     

Cigarette Smoke Stimulates SARS-CoV-2 Internalization by Activating AhR and Increasing ACE2 Expression in Human Gingival Epithelial Cells

A large body of evidence shows the harmful effects of cigarette smoke to oral and systemic health. More recently, a link between smoking and susceptibility to coronavirus disease 2019 (COVID-19) was proposed. COVID-19 is due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which uses the receptor ACE2 and the protease TMPRSS2 for entry into host cells, thereby infecting cells of the respiratory tract and the oral cavity. Here, we examined the effects of cigarette smoke on the expression of SARS-CoV-2 receptors and infection in human gingival epithelial cells (GECs). We found that cigarette smoke condensates (CSC) upregulated ACE2 and TMPRSS2 expression in GECs, and that CSC activated aryl hydrocarbon receptor (AhR) signaling in the oral cells. ACE2 was known to mediate SARS-CoV-2 internalization, and we demonstrate that CSC treatment potentiated the internalization of SARS-CoV-2 pseudovirus in GECs in an AhR-dependent manner. AhR depletion using small interference RNA decreased SARS-CoV-2 pseudovirus internalization in CSC-treated GECs compared with control GECs. Our study reveals that cigarette smoke upregulates SARS-CoV-2 receptor expression and infection in oral cells. Understanding the mechanisms involved in SARS-CoV-2 infection in cells of the oral cavity may suggest therapeutic interventions for preventing viral infection and transmission.     

Constitutive Effects of Lead on Aryl Hydrocarbon Receptor Gene Battery and Protection by β‐carotene and Ascorbic Acid in Human HepG2 Cells

Lead (Pb) is an environmental pollutant that can get entry into human body through contaminated foods, drinks, and inhaled air leading to severe biological consequences, and has been responsible for many deaths worldwide. The objectives of this study were 1st to investigate the modulatory effects of environmentally relevant concentrations of Pb on AhR gene battery, which is controlling xenobiotics metabolism. 2nd, trials to reduce Pb‐induced adverse effects were done using some phytochemicals like β‐carotene or ascorbic acid. Human hepatoma (HepG2) cell lines were exposed to a wide range of Pb concentrations varying from physiological to toxic levels (0 to 10 mg/L) for 24 h. High Pb concentrations (1 to 10 mg/L) significantly reduced phase I (CYP1A1 and 1A2) and phase II (UGT1A6 and NQO1) xenobiotic metabolizing enzyme mRNA expression in a mechanistic manner through the AhR regulation pathway. Additionally, these Pb concentrations induced oxidative stress in HepG2 cells in terms of production of reactive oxygen species (ROS) and induced heme oxygenase‐1 mRNA expression in a concentration‐dependent phenomenon. Coexposure of HepG2 cells to physiological concentrations of some micronutrients, like β‐carotene (10 μM) or ascorbic acid (0.1 mM), along with Pb (1 mg/L) for 24 h significantly reduced the levels of ROS production and recovered AhR mRNA expression into the normal levels. Thus, consumption of foods rich in these micronutrients may help to reduce the adverse effects of lead in areas with high levels of pollution.     

北方某水厂原水及处理过程中Ah受体效应的行为研究

以北方某城市给水厂的自来水为研究对象,采用重组基因酵母测定法对不同处理工艺单元出水的芳香烃受体(AhR)效应进行了检测.检测结果表明,原水具有明显的AhR效应经常规工艺处理后AhR效应不能得到很好的去除,而经臭氧-活性炭深度处理后,92%的AhR效应能够被有效去除.     

Expression of the Aryl Hydrocarbon Receptor in Growth Plate Cartilage and the Impact of Its Local Modulation on Longitudinal Bone Growth

Although dioxin has been reported to impair bone growth in both humans and animals, the underlying mechanisms have not been clarified. We conducted this study to rule out if dioxin may directly target the growth plate, via local modulation of the aryl hydrocarbon receptor (AhR). Initial studies in rare tissue samples of the human growth plate confirmed that the AhR protein is widely expressed in growth plate cartilage. To explore the local role of the AhR, mechanistic studies were performed in a well-established model of cultured fetal rat metatarsal bones. The longitudinal growth of these bones was monitored while being exposed to AhR modulators. The AhR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin, did not affect bone growth at any concentrations tested (1 pM–10 nM). In contrast, the AhR antagonist, alpha-naphthoflavone, suppressed bone growth and increased chondrocyte apoptosis, although only at a high, potentially cytotoxic concentration (50 µM). We conclude that although the AhR is widely expressed in the growth plate, bone growth is not modulated when locally activated, and therefore, dioxin-induced growth failure is likely mediated through systemic rather than local actions.     

人参叶多酚GLP-8调控AhR/NLRP3信号通路抑制BaP诱导的气道上皮细胞炎症因子过表达

基于活性追踪方法分离人参叶多酚化合物（Ginseng leaf polyphenols,GLPs)并研究其抗环境污染物苯并芘（Benzo(a)pyrene,BaP）诱发气道上皮细胞（16HBE）氧化、炎症损伤的作用机制。最终分离、鉴定11个人参叶多酚化合物GLP-1~ GLP-11,其中GLP-8（Albaspidin AA,Ginseng leaf polyphenol-8）能够显著抑制BaP诱导的16HBE细胞损伤;相比于BaP组,GLP-8使16HBE细胞活力提升13.90%;GLP-8使BaP诱导的活性氧（Reactive oxygen species,ROS）过量分泌分别降低了19.30%（5 μg/mL）和41.30%（25 μg/mL）;GLP-8使Bap诱导的16HBE细胞凋亡率分别降低5.80%（5 μg/mL）和9.30%（25 μg/mL）;25 μg/mL GLP-8作用后,BaP诱导的炎症因子IL-33、IL-25、IL-1β及IL-6的表达分别减少60.10%、28.90%、33.50%及41.90%;GLP-8抑制芳香烃受体（AhR）及核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）信号通路激活。因此得出,GLP-8具有通过调控AhR/NLRP3信号通路抑制BaP诱导的ROS过量分泌及炎症因子过表达来发挥保护气道上皮细胞活性的功能。     

Ah receptor agonist activity in frequently consumed food items

The aryl hydrocarbon receptor (AhR) receives much attention for its role in the toxicity of dioxins and dioxin-like polychlorinated biphenyls. However, many other compounds have also been reported to bind and activate AhR, of which natural food components are of special interest from a human health perspective. Using the dioxin receptor–chemical-activated luciferase gene expression (DR CALUX®) bioassay, extracts from many food items frequently consumed in the Netherlands were screened to estimate the intake of natural AhR agonists (NAhRAs). Using the prototypical AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as standard, it was estimated that the daily intake of NAhRAs might be considerably higher than the reported intake of dioxins and dioxin-like polychlorinated biphenyls. Potatoes, cruciferous vegetables, bread, hamburgers, and grapefruit juice contained most NAhRAs. Food preparation and acid treatment can show a significant effect on AhR activation. The interaction of natural and xenobiotic AhR agonists should be taken into account when performing risk–benefit analysis of both types of compounds.