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Triptolide (TL) is an active component of Tripterygium wilfordii Hook. F which is used to treat autoimmune and inflammatory disease. However, a high incidence of adverse effects is often observed in clinic. Previously we have demonstrated that cytochrome P450s (CYPs) are involved in the metabolism of TL and low activity of hepatic P450 reductase aggravates TL-induced toxicity. However, the underlying mechanisms of TL-induced toxicity mediated by hepatic CYPs have not been well delineated. Here, an integrated H NMR-based metabolomic analysis was performed to evaluate the global biochemical alteration in the liver-specific cytochrome P450 reductase (CPR) knockout (KO) mice and wild-type (WT) counterparts with a same dose of TL (0.5 mg/kg) administration. Dramatically different metabolic profiles indicated more severe hepatotoxicity and nephrotoxicity induced by TL in KO mice than in WT mice, which were confirmed by serum biochemistry and histopathological examination. Furthermore, the results from both multivariate statistical analysis and system statistical metabolic correlation analysis indicated that the significantly changed endogenous metabolites were primarily involved in oxidative stress, energy metabolism, amino acid metabolism, gut microflora metabolism, and choline metabolism. Our results reveal the molecular mechanisms of TL-induced toxicity in the condition of hepatic CYP inactivation. As CYP inactivation and/or inhibition are usually caused by genetic polymorphism and/or drug-drug interactions, personalized prescription according to enzyme activity of CYPs and metabolic profiling could be used to maximize therapeutic efficacy and avoid or reduce TL-induced toxicity clinically. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]