Toxicity of triptolide not due to inhibition of CYPs

Triptolide, a purified component of a traditional Chinese Medicine, has been shown to have anti-inflammatory, antifertility, antineoplastic, and immunosuppressive activity, however, its clinical usage is limited to some extent due to its toxicity. The aim is to discover the correlation of triptolide toxicity with cytochrome P450 (CYPs). METHODE The metabolism properties and the inhibitory effects against cytochrome P450 (CYPs) of triptolide were studied in vitro. Triptolide was incubated with human liver microsome in the presence of NADPH-generating system. The inhibitory effects of triptolide (5μM, 50μM) against the activities of seven CYP isoforms including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 were examined in human liver microsomes (HLM). To identify time-dependent inhibition, triptolide (50μM, 500μM) was preincubated with microsomes and NADPH-generating system for 0-60 min, and then the extent of inhibition towards seven CYP isoforms were examined. RESULTS Triptolide was slightly NADPH-dependently metabolized in HLM, and four possible products were detected by HPLC. There were no inhibitory effects against tested CYPs activities or time- and NADPH- dependent inhibition against tested CYPs found. CONCLUSION Triptolide was slightly NADPH-dependently metabolized in HLM. And the toxicity of triptolide has no relevance with CYPs inhibition or CYPs-mediated bioactivation. \n\nKey words: triptolide; cytochrome P450; metabolism; inhibition.