佐米曲坦诱导雄性大鼠肝CYP3A2的作用机制

Induction study of CYP3A2 in male rats by zolmitriptan

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。

In our preliminary studies, we observed zolmitriptan （ZOL） treatment led to induction of CYP3A2 in male not female rats. To figure out the reason is of great significance for drug-drug interactions and personalized administration. Since growth hormone （GH） is known as the major mechanistic determinant of sexually-dimorphic gene expression like CYP3A2 in rat liver, the impacts of ZOL on both plasma GH levels in non monosodium glutamate （MSG）-treated rats and CYP3A2 expression in GH depleted MSG-treated rats were studied. ZOL was shown to partially suppress GH levels in both genders. Furthermore, CYP3A2 protein and mRNA level declined in male not female MSG-treated rats. In order to study the possible molecular events involved in the depression of GH and gender-selective induction on rat CYP3A2 by ZOL, the mRNA and protein level （whole protein and nuclear protein） of hepatocyte nuclear factor 4 a （HNF4α） was investigated. Nuclear accumulation of HNF4a was observed in the normal male not female rat liver tissue following ZOL treatment. However, this kind of nuclear translocation did not occur in rat hepatocytes and MSG-treated rats. These findings demonstrated CYP3A2 inducibility by ZOL was gender-selective. GH and HNF4α may play an important role in CYP3A2 induction.