title: Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity.
abstract: Triptolide, the primary active component of Tripterygium wilfordii Hook F, has various pharmacological activities but also a narrow therapeutic window. Cytochrome P450s are proposed to be responsible for the hydroxylation of triptolide in vitro and CYP3A induction by dexamethasone can increase the metabolism of triptolide and decrease the hepatotoxicity in rat. However, triptolide-induced toxicity has not been investigated in an animal model having a suppression of P450 activities. Here we compared the toxicological effects and toxicokinetics of triptolide between liver-specific cytochrome P450 reductase (CPR) knockout (KO) mice (abolished hepatic P450 activities) and wild-type (WT) control mice after a single oral gavage of triptolide at 0.5mg/kg or 1.0mg/kg. A low toxic dose of triptolide at 0.5mg/kg for WT mice resulted in severe toxicities including death in KO mice. Changes in serum biochemistry, hematology and histopathology further indicated much more severe toxicities in multiple organs in KO mice compared to WT mice after triptolide administration. The mono-hydroxylated metabolites of triptolide detected in the blood of WT mice were undetectable in KO mice, accompanied by much higher triptolide levels in the blood and tissues including the liver, kidney, and spleen determined by LC-MS/MS. Taken together, our results confirmed that inactivation of hepatic P450s abolishes the ability in metabolism of triptolide in the liver, subsequently resulting in an increase in bioavailability and toxicity of triptolide in vivo. It is suggested that P450 inhibition/inactivation might pose a significant health risk in the clinic use of triptolide.
authors: Center for Drug Safety Evaluation and Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Xiang
authors: X
authors: Xue
authors: Likun
authors: L
authors: Gong
authors: Xinming
authors: X
authors: Qi
authors: Yuanfeng
authors: Y
authors: Wu
authors: Guozhen
authors: G
authors: Xing
authors: Jun
authors: J
authors: Yao
authors: Yang
authors: Y
authors: Luan
authors: Ying
authors: Y
authors: Xiao
authors: Yan
authors: Y
authors: Li
authors: Xiongfei
authors: X
authors: Wu
authors: Min
authors: M
authors: Chen
authors: Jun
authors: J
authors: Gu
authors: Jin
authors: J
authors: Ren