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提取物通过调节组成型雄烷受体/孕烷 X 受体通路保护 HaCaT 细胞免受菲诱导的毒性。

Extract Protects HaCaT Cells against Phenanthrene-Induced Toxicity through the Regulation of Constitutive Androstane Receptor/Pregnane X Receptor Pathway.

机构信息

Natural Products for Neuroprotection and Anti-Ageing Research Unit, Chulalongkorn University, Bangkok 10330, Thailand.

Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

出版信息

Nutrients. 2022 Sep 16;14(18):3829. doi: 10.3390/nu14183829.

DOI:10.3390/nu14183829
PMID:36145217
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9502750/
Abstract

Phenanthrene (Phe) exposure is associated with skin ageing, cardiotoxicity and developmental defects. Here, we investigated the mode of Phe toxicity in human keratinocytes (HaCaT cells) and the attenuation of toxicity on pre-treatment (6 h) with ethanol extract of calyxes (HS). Cell viability, reactive oxygen species (ROS) generation, mitochondrial membrane potential (ΔΨm) alteration, changes in the transcriptional activity of selected genes involved in phase I and II metabolism, antioxidant response and gluconeogenesis, western blot and docking studies were performed to determine the protective effect of HS against Phe. Phe (250 μM) induced cytotoxicity in HaCaT cells through AhR-independent, CAR/PXR/RXR-mediated activation of CYP1A1 and the subsequent alterations in phase I and II metabolism genes. Further, CYP1A1 activation by Phe induced ROS generation, reduced ΔΨm and modulated antioxidant response, phase II metabolism and gluconeogenesis-related gene expression. However, pre-treatment with HS extract restored the pathological changes observed upon Phe exposure through CYP1A1 inhibition. Docking studies showed the site-specific activation of PXR and CAR by Phe and inhibition of CYP1A1 and CYP3A4 by the bioactive compounds of HS similar to that of the positive controls tested. Our results conclude that HS extract can attenuate Phe-induced toxicity in HaCaT cells through CAR/PXR/RXR mediated inhibition of CYP1A1.

摘要

菲（Phe）暴露与皮肤老化、心脏毒性和发育缺陷有关。在这里，我们研究了 Phe 对人角质形成细胞（HaCaT 细胞）的毒性作用方式，以及用萼乙醇提取物（HS）预处理（6 小时）对毒性的减弱作用。进行细胞活力、活性氧（ROS）生成、线粒体膜电位（ΔΨm）改变、参与 I 期和 II 期代谢、抗氧化反应和糖异生的选定基因的转录活性变化、western blot 和对接研究，以确定 HS 对 Phe 的保护作用。Phe（250 μM）通过 AhR 非依赖性、CAR/PXR/RXR 介导的 CYP1A1 激活以及随后的 I 期和 II 期代谢基因的改变，在 HaCaT 细胞中诱导细胞毒性。此外，Phe 诱导的 CYP1A1 激活会导致 ROS 生成、降低 ΔΨm 并调节抗氧化反应、II 期代谢和与糖异生相关的基因表达。然而，HS 提取物预处理通过抑制 CYP1A1 恢复了 Phe 暴露引起的病理变化。对接研究表明 Phe 特异性激活了 PXR 和 CAR，HS 的生物活性化合物抑制了 CYP1A1 和 CYP3A4，与测试的阳性对照相似。我们的研究结果表明，HS 提取物可以通过 CAR/PXR/RXR 介导的 CYP1A1 抑制来减轻 Phe 诱导的 HaCaT 细胞毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/10e0a7c05f81/nutrients-14-03829-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/8ecd2c393a91/nutrients-14-03829-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/10e0a7c05f81/nutrients-14-03829-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/eb8fba318628/nutrients-14-03829-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/3e04e8dead8e/nutrients-14-03829-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/e8eb748e01bd/nutrients-14-03829-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/ee988bf539e9/nutrients-14-03829-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/6397a97e69b1/nutrients-14-03829-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/03bb0549f837/nutrients-14-03829-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/8ecd2c393a91/nutrients-14-03829-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/35cf/9502750/10e0a7c05f81/nutrients-14-03829-g012.jpg

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[3]
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[4]
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本文引用的文献

[1]
L. Leaf Extracts and Their Metabolites Inhibit the Aryl Hydrocarbon Receptor (AhR) Activation In Vitro and in Human Keratinocytes: Potential Impact on Inflammatory Skin Diseases and Skin Cancer.

Molecules. 2022-4-13

[2]
Establishment of cytochrome P450 1a gene-knockout Javanese medaka, Oryzias javanicus, which distinguishes toxicity modes of the polycyclic aromatic hydrocarbons, pyrene and phenanthrene.

Mar Pollut Bull. 2022-5

[3]
Toxic mechanism on phenanthrene-triggered cell apoptosis, genotoxicity, immunotoxicity and activity changes of immunity protein in Eisenia fetida: Combined analysis at cellular and molecular levels.

Sci Total Environ. 2022-5-1

[4]
In vitro profiling of toxic effects of environmental polycyclic aromatic hydrocarbons on nuclear receptor signaling, disruption of endogenous metabolism and induction of cellular stress.

Sci Total Environ. 2022-4-1

[5]
L. Extract Protects Hippocampal Neuronal Cells against PAHs-Induced Neurotoxicity: Possible Active Constituents Include Stigmasterol and Vitamin E.

Nutrients. 2021-7-10

[6]
An activity-based fluorescent sensor for the detection of the phenol sulfotransferase SULT1A1 in living cells.

RSC Chem Biol. 2021-3-15

[7]
Toxic mechanism on phenanthrene-induced cytotoxicity, oxidative stress and activity changes of superoxide dismutase and catalase in earthworm (Eisenia foetida): A combined molecular and cellular study.

J Hazard Mater. 2021-9-15

[8]
Long-term exposure to environmental levels of phenanthrene disrupts spermatogenesis in male mice.

Environ Pollut. 2021-9-15

[9]
An integrated virtual screening and drug repurposing strategy for the discovery of new antimalarial drugs against Plasmodium falciparum phosphatidylinositol 3-kinase.

J Cell Biochem. 2021-10

[10]
Antioxidant and reduced skin-ageing effects of a polyphenol-enriched dietary supplement in response to air pollution: a randomized, double-blind, placebo-controlled study.

Food Nutr Res. 2021-3-29

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