Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol
Sex hormones regulate cerebral drug metabolism via brain miRNAs: down-regulation of brain CYP2D by androgens reduces the analgesic effects of tramadol
复制标题
性激素通过脑 miRNA 调节脑药物代谢：雄激素下调脑 CYP2D 降低曲马多的镇痛作用
DOI：
10.1111/bph.13206
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发表时间：
2015-10-01
影响因子：
7.3
通讯作者：
Yue, Jiang
中科院分区：
文献类型：
--
作者：
Li, Jie;Xie, Mengmeng;Yue, Jiang
背景与目的脑细胞色素P4502D代谢外源性神经毒素、内源性物质和神经递质。大脑中的细胞色素P450 2 D可以通过器官特异性的方式进行调节，但可能的调节机制还不太清楚。本研究探讨了miRNAs参与睾酮对脑内细胞色素P450脱氢酶的选择性调节，以及睾酮对曲马多药理图谱的相应改变。采用SH-SY5Y细胞、U251细胞、HepG2细胞以及睾丸切除生长激素受体基因敲除(GHR-KO)小鼠和大鼠，研究了睾酮对细胞色素P450脱氢酶和脑富集型miRNAs的调节作用。用微透析法测定曲马多在大鼠脑内的浓度-时间曲线。大鼠甩尾实验评价曲马多的镇痛作用。Key ResultsmiR-101和miR-128-2结合了CYP2D6mRNA的3-非翻译区，并降低了其水平。在SH-SY5Y和U251细胞中，睾酮通过上调miR-101和miR-128-2来降低细胞色素P450-2D6的催化功能，而在HepG2细胞中无此作用。切除降低了雄性GHR-KO小鼠海马区miR-101和miR-128-2的水平，表明雄激素直接调节miRNAs，而不是通过改变生长激素的分泌模式。睾丸切除后曲马多的药代动力学和药效学变化可被补充睾酮或脑内特定的细胞色素P450 2 D抑制剂减弱。结论和意义通过脑内丰富的miRNAs选择性调节脑内细胞色素2磷酸酶，跟随雄激素水平的变化，如睾酮治疗、雄激素剥夺治疗和/或衰老，可能会改变对中枢活性物质的反应。
Background and PurposeBrain cytochrome P450 2D (CYP2D) metabolises exogenous neurotoxins, endogenous substances and neurotransmitters. Brain CYP2D can be regulated in an organ-specific manner, but the possible regulatory mechanisms are poorly understood. We investigated the involvement of miRNAs in the selective regulation of brain CYP2D by testosterone and the corresponding alteration of the pharmacological profiles of tramadol by testosterone.Experimental ApproachThe regulation of CYP2D and brain-enriched miRNAs by testosterone was investigated using SH-SY5Y cells, U251 cells, and HepG2 cells as well as orchiectomized growth hormone receptor knockout (GHR-KO) mice and rats. Concentration-time curves of tramadol in rat brain were determined using a microdialysis technique. The analgesic action of tramadol was assessed by the tail-flick test in rats.Key ResultsmiR-101 and miR-128-2 bound the 3-untranslated region of the CYP2D6 mRNA and decreased its level. Testosterone decreased CYP2D6 catalytic function via the up-regulation of miR-101 and miR-128-2 in SH-SY5Y and U251 cells, but not in HepG2 cells. Orchiectomy decreased the levels of miR-101 and miR-128-2 in the hippocampus of male GHR-KO mice, indicating that androgens regulate miRNAs directly, not via the alteration of growth hormone secretion patterns. Changes in the pharmacokinetic and pharmacodynamic profiles of tramadol by orchiectomy was attenuated by either testosterone supplementation or a specific brain CYP2D inhibitor.Conclusions and ImplicationsThe selective regulation of brain CYP2D via brain-enriched miRNAs, following changes in androgen levels, such as in testosterone therapy, androgen deprivation therapy and/or ageing may alter the response to centrally active substances.