Molecular mechanism of chemical-induced toxicity in fetal livers

化学品致胎儿肝脏毒性的分子机制

基本信息

批准号：
17390034
负责人：
YAMAZAKI Hiroshi
金额：
$ 10.07万
依托单位：
Showa Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

We found several new results of drug metabolism in human liver microsomes. 1) Voriconazole ((2R, 3S)-2-(2, 4-difluorophenyI)-3-(5-fluoro-4-pyrimidiny1)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol) is a new antifungal agent developed as oral and intravenous formulations. In vivo studies in humans have indicated that voriconazole is extensively metabolized with less than 2% of the dose excreted unchanged. Involvement of cytochrome CYP2C19, CYP2C9, and CYP3A4 in N-oxidation of voriconazole has been demonstrated using human liver microsomes. To confirm the precise roles of P450 isoforms in voriconazole clearance in individuals, we investigated the oxidative metabolism of voriconazole catalyzed by recombinant P450s as well as human liver microsomes genotyped for the CYP2C19 gene. Among recombinant P450 isoforms using Escherichia coli expression systems, CYP2C19 and CYP3A4 had voriconazole N-oxidation activities, but not CYP2C92) Propofol (2, 6-diisopropylphenol) is administered for the induction … More of anesthesia and maintenance of anesthesia or for sedation. The merit of rapid and complete recovery that occurs even after relatively prolonged intravenous infusions of propofol is attributable to the extensive biotransformation of the parent compound, primarily in the liver. However, a significant association with the development of progressive myocardial failure has been reported for long-term and high-dose propofol infusion. Although there are several reports on the propofol pharmacokinetics and drug interactions in humans, the roles of individual P450 enzymes in the propofol disposition are still unknown. In the present study, the roles of human P450 enzymes involved in propofol 4- and ω-hydroxylation were investigated with recombinant human P450s and liver microsomes. CYP2B6 and CYP1A2, followed CYP3A4, showed high activities of propofol 4-hydroxylation in recombinant human P450 enzyme systems. In the contrast, ω-hydroxylation of propofol was mainly catalyzed by CYP2B6.3) Thalidomide is a promising drug in the treatment of a number of cancers and inflammatory diseases. On the other hand, a little information was reported regarding effects on metabolizing enzymes. We investigated the effects of thalidomide on cytochrome P450 in human liver microsomes. The present results suggest that total midazolam clearance would be increased in a dose dependent manner. Thalidomide may cause drug interactions of co-administered medicines Less

我们发现了人肝微粒体中药物代谢的几个新结果。 1）伏立康唑（（（2R，3S）-2-（2，4-二氟po）-3-（5-fluoro-4-4- pyrimidiny1）-1-（1H-1，2，4-三唑-1-基）-2-叔丁醇）是一种新的抗真菌剂，是一种新的抗真菌剂，是口腔和抗精神经会形式的新抗真菌剂。人类的体内研究表明，伏立康唑被广泛代谢，不到剂量过量不变的2％。使用人肝微粒体证明了细胞色素CYP2C19，CYP2C9和CYP3A4参与伏立康唑的N氧化。为了确认P450同工型在个体中伏立康唑清除率中的确切作用，我们研究了重组P450催化的伏立康唑的氧化代谢以及人肝微粒体基因型，用于CYP2C19基因。在使用大肠杆菌表达系统的重组P450同工型中，CYP2C19和CYP3A4具有伏立康唑N氧化活性，但不具有CYP2C92）丙泊酚（2，2，6-二甲丙基苯酚），以进行诱导……更多的麻醉和维持静脉曲张或替代。即使在相对延长的提案静脉内输注后，快速和完整恢复的优点也归因于肝脏中主要的主要化合物的广泛生物转化。但是，据报道，长期和高剂量提案输注的进行性心肌衰竭的发展有着显着关联。尽管关于人类提案的药代动力学和药物相互作用的报告有几份报告，但单个P450酶在提案处置中的作用仍然未知。在本研究中，使用重组人P450和肝微粒体研究了参与提案4和ω-羟基化的人类P450酶的作用。 CYP2B6和CYP1A2紧随其后的CYP3A4，在重组人P450酶系统中表现出高度的4-羟基化活性。相比之下，提案的ω-羟基化主要是由CYP2B6.3催化的，Thalidomide是一种在治疗多种癌症和炎症性疾病的治疗方面的承诺药物。另一方面，报告了有关对代谢酶的影响的一些信息。我们研究了沙利度胺对人肝微粒体中细胞色素P450的影响。目前的结果表明，总咪达唑仑清除率将以剂量依赖的方式增加。沙利度胺可能会导致共同管理药物的药物相互作用较少