佐米曲坦诱导雄性大鼠肝CYP3A2的作用机制

发布时间：2018-09-05 09:35

【摘要】：作者前期研究发现佐米曲坦(ZOL)对雄性大鼠肝中CYP3A2具有诱导作用,而对雌性大鼠没有诱导作用。阐明其机制对于研究ZOL的药物相互作用和个体化用药具有积极意义。由于生长激素(GH)与一些蛋白的性别差异性表达密切相关,因此,本研究探究了ZOL对大鼠GH分泌的影响,以及其对脑垂体化学损伤大鼠模型肝中CYP3A2的诱导作用。结果发现,ZOL可以抑制正常大鼠体内血浆GH水平。与正常组大鼠的诱导结果不同,ZOL抑制了损伤组雄性大鼠肝中CYP3A2的表达。另外,ZOL对于雌雄原代肝细胞中的CYP3A1/2无明显诱导作用。进一步研究发现,给予ZOL后正常雄性大鼠肝中肝细胞核因子4α(HNF4α)的入核水平明显增加,而正常雌性大鼠、脑垂体化学损伤大鼠和大鼠原代肝细胞中HNF4α的入核水平无明显变化。结果表明,GH和HNF4α在ZOL性别差异性诱导CYP3A2的过程中发挥了重要的作用。
[Abstract]:In previous studies, we found that Zomitriptan (ZOL) could induce CYP3A2 in the liver of male rats, but not in female rats. It is of great significance to elucidate its mechanism for the study of drug interaction and individualized drug use in ZOL. Since the expression of growth hormone (GH) is closely related to the sex difference of some proteins, this study investigated the effect of ZOL on the secretion of GH in rats and on the induction of CYP3A2 in the liver of the rat model with chemical injury of pituitary gland. The results showed that ZOL could inhibit the level of plasma GH in normal rats. Different from the normal rats, ZOL inhibited the expression of CYP3A2 in the liver of the injured rats. In addition, ZOL did not induce CYP3A1/2 in primary hepatocytes of both sexes. It was found that the nucleation level of nuclear factor 4 伪 (HNF4 伪) in the liver of normal male rats was significantly increased after ZOL administration, while that of HNF4 伪 in the primary hepatocytes of normal female rats and primary hepatocytes of the normal female rats did not change significantly. The results showed that GH and HNF4 伪 played an important role in the process of inducing CYP3A2 by sex difference of ZOL.
【作者单位】： 浙江大学药学院药物代谢和药物分析研究所浙江省抗肿瘤药物研究重点实验室;
【基金】：国家自然科学基金资助项目(30600772)
【分类号】：R965

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