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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

我们在人肝微粒体中发现了一些药物代谢的新结果。1)伏立康唑（Voriconazole）（（2 R，3S）-2-（2，4-difluorophenyl）-3-（5-fluoro-4-pyrimidinyl）-1-（1H-1，2，4-triazole-1-yl）-2-butanol）是一种新型抗真菌药物。人体体内研究表明，伏立康唑被广泛代谢，以低于2%的剂量原型排泄。已使用人肝微粒体证明细胞色素CYP 2C 19、CYP 2C 9和CYP 3A 4参与伏立康唑的N-氧化。为了证实P450亚型在个体伏立康唑清除中的确切作用，我们研究了重组P450催化的伏立康唑氧化代谢以及CYP 2C 19基因分型的人肝微粒体。在使用大肠杆菌表达系统的重组P450亚型中，CYP 2C 19和CYP 3A 4具有伏立康唑N-氧化活性，但CYP 2C 92不具有。 ...更多信息麻醉和维持麻醉或镇静。即使在相对长时间静脉输注丙泊酚后也能快速完全恢复的优点可归因于母体化合物的广泛生物转化，主要是在肝脏中。然而，据报道，长期和高剂量丙泊酚输注与进展性心肌衰竭的发生显著相关。虽然有一些关于丙泊酚在人体内的药代动力学和药物相互作用的报道，但单个P450酶在丙泊酚处置中的作用仍然未知。在本研究中，人P450酶参与丙泊酚4-和ω-羟基化的作用进行了研究与重组人P450和肝微粒体。在重组人P450酶系统中，CYP 2B 6和CYP 1A 2表现出较高的丙泊酚4-羟基化活性，其次是CYP 3A 4。而丙泊酚的ω-羟基化反应主要由CYP 2B 6催化。3）沙利度胺是一种很有前途的治疗多种癌症和炎性疾病的药物。另一方面，关于对代谢酶的影响，报告的信息很少。我们研究了沙利度胺对人肝微粒体细胞色素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性方式增加。沙利度胺可能会导致联合用药的药物相互作用减