Autoinduction of cytochrome P450 (P450) 3A4-mediated metabolism of thalidomide was investigated in humanized-liver mice and human hepatocyte-derived HepaSH cells. The mean plasma ratios of 5-hydroxythalidomide and glutathione adducts to thalidomide were significantly induced (3.5- and 6.0-fold, respectively) by thalidomide treatment daily at 1000 mg/kg for 3 days and measured at 2 h after the fourth administration (on day 4). 5-Hydroxythalidomide was metabolically activated by P450 3A4 in HepaSH cells pretreated with 300 and 1000 μM thalidomide, and 5,6-dihydroxythalidomide was detected. Significant induction of P450 3A4 mRNA expression (4.1-fold) in the livers of thalidomide-treated mice occurred. Thalidomide exerts a variety of actions through multiple mechanisms following bioactivation by induced human P450 3A enzymes.

中文翻译：

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沙利度胺在人源化肝小鼠和实验人肝细胞 HepaSH 细胞中体内和体外诱导细胞色素 P450 3A4


在人源化肝小鼠和人肝细胞来源的 HepaSH 细胞中研究了细胞色素 P450 (P450) 3A4 介导的沙利度胺代谢的自诱导。每天以 1000 mg/kg 的沙利度胺治疗 3 天，显着诱导 5-羟基沙利度胺和谷胱甘肽加合物与沙利度胺的平均血浆比率（分别为 3.5 倍和 6.0 倍），并在第四次给药后 2 小时（当天）进行测量。 4).在用 300 和 1000 μM 沙利度胺预处理的 HepaSH 细胞中，5-羟基沙利度胺被 P450 3A4 代谢激活，并检测到 5,6-二羟基沙利度胺。沙利度胺治疗小鼠肝脏中 P450 3A4 mRNA 表达显着诱导（4.1 倍）。沙利度胺被诱导的人类 P450 3A 酶生物激活后，通过多种机制发挥多种作用。