Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment
Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment
复制标题
实验诱发急性肺损伤的低氧血症大鼠肝脏药物代谢活性的改变
DOI：
10.1080/00498254.2017.1349969
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发表时间：
2018
期刊：
影响因子：
1.8
通讯作者：
Aiba T
中科院分区：
文献类型：
--
作者：
Hori Y;Shimizu Y;Aiba T
1.用实验性急性肺损伤（ALI）大鼠低氧血症肝微粒体体外研究肝脏药物代谢活性。雄性Wistar大鼠支气管内给药稀释盐酸溶液诱导ALI。制备正常大鼠和ALI大鼠肝微粒体，用细胞色素P450 (CYP) 3a对肝脏药物代谢进行孵育研究。与正常大鼠相比，ALI大鼠nadph依赖性代谢显著增加。睾酮6 - β-羟基化在ALI大鼠中也显著增加。检测肝脏CYP3A蛋白表达时，ALI大鼠的CYP3A1蛋白表达显著升高，而CYP3A2蛋白表达不变。nadph -细胞色素P450还原酶（POR）是一种在cypp介导的药物代谢中介导电子转移的蛋白质，其肝脏表达也在ALI大鼠中显著增加。根据有关咪达唑仑消除的研究结果，肝脏药物代谢活性似乎在急性低氧血症的反应中增加，部分原因是CYP3A酶的表达改变，并且随着POR表达的增加，电子转移的增强可能与这种增加有关。
1. Hepatic drug-metabolizing activity was investigatedin vitrowith liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI).2. Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3 A was examined in an incubation study with the microsomes.3. The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats. Testosterone 6β-hydroxylation was also observed to significantly increase in ALI rats.4. When the hepatic expression of CYP3A proteins was examined, the protein expression of CYP3A1 was shown to significantly increase and that of CYP3A2 remained unaltered in ALI rats. The hepatic expression of NADPH-cytochrome P450 reductase (POR), a protein mediating electron transfer in CYP-mediated drug metabolism, was also revealed to significantly increases in ALI rats.5. With the findings regarding the midazolam elimination, the hepatic drug-metabolizing activity seems to increase in response to acute hypoxemia, partly due to an altered expression of the CYP3A enzymes, and an augmented electron transfer with an increased POR expression is probably involved in the increase.