The Aryl Hydrocarbon Receptor Activator Benzo[a]pyrene Enhances Vitamin D3 Catabolism in Macrophages
The Aryl Hydrocarbon Receptor Activator Benzo[a]pyrene Enhances Vitamin D3 Catabolism in Macrophages
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DOI：
10.1093/toxsci/kfp044
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发表时间：
2009-05-01
影响因子：
3.8
通讯作者：
Makishima, Makoto
中科院分区：
文献类型：
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作者：
Matsunawa, Manabu;Amano, Yusuke;Makishima, Makoto
苯并[a]芘（BaP）是香烟燃烧产生的一种多环芳烃，被认为是吸烟相关癌症和动脉粥样硬化的致病因子。1,25 - 二羟基维生素D₃ [1,25(OH)₂D₃] 是核受体维生素D受体（VDR）的强效配体，已被证明可降低骨质疏松症、某些类型癌症和心血管疾病的风险，这表明维生素D₃与吸烟的作用相反。在本研究中，我们探究了BaP对维生素D₃信号通路的影响。在人单核细胞/巨噬细胞衍生的THP - 1细胞和乳腺癌MCF - 7细胞中，BaP有效地增强了1,25(OH)₂D₃依赖性的细胞色素P450 24A1（CYP24A1）诱导作用。在THP - 1细胞中，BaP联合用药对CD14、花生四烯酸5 - 脂氧合酶和抗菌肽cathelicidin的mRNA表达影响较小或无影响。BaP还增强了非维生素D类VDR配体醋酸石胆酸诱导的CYP24A1表达。另一种芳香烃受体（AhR）配体2,3,7,8 - 四氯二苯并 - 对 - 二噁英增强了1,25(OH)₂D₃在THP - 1细胞中对CYP24A1的表达诱导作用。用AhR拮抗剂和蛋白质合成抑制剂处理细胞可抑制BaP对CYP24A1诱导的增强作用，这表明BaP的作用是通过AhR激活和从头合成蛋白质来介导的。BaP预处理增加了1,25(OH)₂D₃依赖性的VDR和维甲酸X受体向CYP24A1启动子的募集。对1,25(OH)₂D₃代谢的分析表明，BaP增强了THP - 1细胞中CYP24A1对1,25(OH)₂D₃的羟基化作用。因此，BaP激活AhR可刺激维生素D₃分解代谢。AhR对维生素D信号的调节可能是吸烟相关疾病的潜在机制之一。
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon produced by cigarette combustion, is implicated as a causative agent in smoking-related cancer and atherosclerosis. 1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3], a potent ligand for the nuclear receptor vitamin D receptor (VDR), has been shown to decrease the risk of osteoporosis, some types of cancer and cardiovascular disease, suggesting an opposing effect of vitamin D-3 to cigarette smoking. In this study, we investigated the effects of BaP on the vitamin D-3 signaling pathway. BaP effectively enhanced the 1,25(OH)(2)D-3-dependent induction of cytochrome P450 24A1 (CYP24A1) in human monocyte/macrophage-derived THP-1 cells and breast cancer MCF-7 cells. BaP combination was less or not effective on mRNA expression of CD14, arachidonate 5-lipoxygenase, and cathelicidin antimicrobial peptide in THP-1 cells. BaP also increased the expression of CYP24A1 induced by a non-vitamin D VDR ligand, lithocholic acid acetate. Another aryl hydrocarbon receptor (AhR) ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, enhanced CYP24A1 expression by 1,25(OH)(2)D-3 in THP-1 cells. Treatment of cells with an AhR antagonist and a protein synthesis inhibitor inhibited the enhancing effect of BaP on CYP24A1 induction, indicating that the effects of BaP are mediated by AhR activation and de novo protein synthesis. BaP pretreatment increased 1,25(OH)(2)D-3-dependent recruitment of VDR and retinoid X receptor to the CYP24A1 promoter. Analysis of 1,25(OH)(2)D-3 metabolism showed that BaP enhanced the hydroxylation of 1,25(OH)(2)D-3 by CYP24A1 in THP-1 cells. Thus, AhR activation by BaP stimulates vitamin D-3 catabolism. Modulation of vitamin D signaling by AhR may represent a mechanism underlying cigarette smoking-related diseases.