Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3-24-hydroxylase (CYP24A1).
Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3-24-hydroxylase (CYP24A1).
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DOI：
10.1210/en.2007-0903
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发表时间：
2008-04
期刊：
影响因子：
4.8
通讯作者：
K. Shankar;Xiaoli Liu;Rohit Singhal;Jin-Ran Chen;S. Nagarajan;T. Badger;M. Ronis
中科院分区：
文献类型：
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作者：
K. Shankar;Xiaoli Liu;Rohit Singhal;Jin-Ran Chen;S. Nagarajan;T. Badger;M. Ronis
长期滥用乙醇 (EtOH) 导致的骨质流失常常伴随着维生素 D3 稳态的改变。在当前的研究中，我们研究了乙醇对雌性大鼠模型的影响，其中对照或含乙醇的饮食被灌胃。 EtOH 治疗降低血浆 1,25-二羟基胆钙化醇 (1,25 (OH)2 D3)，同时肾 CYP27B1 (25(OH)D3 1α-羟化酶) mRNA 减少，肾 CYP24A1 (1,25 (OH)2 D3-24-羟化酶) 表达增加。 EtOH 对 CYP24A1 的诱导是由于转录增加而发生的，并且也在体外大鼠肾近端小管细胞 (RPTC) 和 NRK-52E 细胞的原代培养物中观察到。观察到 EtOH 与 1,25 (OH)2 D3 组合对 CYP24A1 的协同诱导作用。 RPTC 中主要的乙醇代谢酶乙醇脱氢酶-1 和 CYP2E1 是由乙醇诱导的。 4-甲基吡唑对乙醇代谢的抑制抑制了 CYP24A1 mRNA 的诱导。 RPTC 中 CYP24A1 mRNA 的诱导也受到蛋白质合成抑制剂放线菌酮的抑制。过氧化氢处理后也诱导了 CYP24A1，并且 RPTC 的 EtOH 处理导致活性氧的产生，如使用荧光探针二氯荧光素乙酸酯通过流式细胞术测量的。此外，用 MAPK 激酶抑制剂 U0126 或 p38 抑制剂 SB203580 抑制 MAPK 信号通路可抑制 EtOH 对 CYP24A1 的诱导。我们的数据表明，由于 CYP24A1 诱导，EtOH 降低了循环 1,25 (OH)2 D3 浓度，而 CYP24A1 诱导是通过 MAPK 激活介导的，而 MAPK 激活是由 EtOH 通过 CYP2E1 和抗利尿激素 1 局部代谢产生的肾脏氧化应激而介导的。
Bone loss resulting from chronic ethanol (EtOH) abuse is frequently accompanied by altered vitamin D3 homeostasis. In the current study, we examined EtOH effects in a female rat model in which control or EtOH-containing diets were infused intragastrically. EtOH treatment reduced plasma 1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) coincident with a decrease in renal CYP27B1 (25(OH)D3 1alpha-hydroxylase) mRNA and an increase in expression of renal CYP24A1 (1,25 (OH)2 D3- 24-hydroxylase). EtOH induction of CYP24A1 occurred as a result of increased transcription and was also observed in vitro in primary cultures of rat renal proximal tubule cells (RPTCs) and in NRK-52E cells. Synergistic induction of CYP24A1 by EtOH in combination with 1,25 (OH)2 D3 was observed. The major EtOH metabolizing enzymes, alcohol dehydrogenase-1 and CYP2E1, were induced by EtOH in RPTCs. Inhibition of EtOH metabolism by 4-methylpyrazole inhibited the induction of CYP24A1 mRNA. CYP24A1 mRNA induction in RPTCs was also inhibited by the protein synthesis inhibitor cycloheximide. CYP24A1 was also induced after hydrogen peroxide treatment, and EtOH treatment of RPTCs resulted in production of reactive oxygen species as measured by flow cytometry using the fluorescent probe dichlorofluorescin acetate. In addition, inhibition of MAPK signaling pathways with the MAPK kinase inhibitor U0126 or the p38 inhibitor SB203580 inhibited EtOH induction of CYP24A1. Our data suggest that EtOH reduces circulating 1,25 (OH)2 D3 concentrations as the result of CYP24A1 induction that is mediated via MAPK activation resulting from renal oxidative stress produced by local metabolism of EtOH via CYP2E1 and antidiuretic hormone-1.