PT  - JOURNAL ARTICLE
AU  - Xu Mao
AU  - Zi xia Hu
AU  - Qian Wang
AU  - Na Zhang
AU  - Shen zhi Zhou
AU  - Ying Peng
AU  - Jiang Zheng
TI  - Nitidine Chloride is a Mechanism-based inactivator of CYP2D6
AID  - 10.1124/dmd.117.079780
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.117.079780
4099  - http://dmd.aspetjournals.org/content/early/2018/05/17/dmd.117.079780.short
4100  - http://dmd.aspetjournals.org/content/early/2018/05/17/dmd.117.079780.full
AB  - Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. NC has been reported to reveal multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after 15 min incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4.36 μM, kinact of 0.052 min-1, and partition ratio of approximately 290. Moreover, the loss of CYP2D6 activity required the presence of NADPH. Superoxide dismutase/catalase and glutathione showed minor protection against the NC-induced enzyme inhibition. Quinidine as a competitive inhibitor of CYP2D6 slowed down the inactivation by NC. Trapping experiments using N-acetylcysteine demonstrated that quinone and/or carbene intermediate were/was generated in human liver microsomal incubations with NC. In addition, potassium ferricyanide prevented the enzyme from the inactivation mediated by NC, which provided evidence that inhibition of CYP2D6 resulted from heme destruction by the formation of a carbene-iron complex. CYP1A2 was found to be the major enzyme involved in the generation of NC quinone metabolites. In conclusion, NC is a mechanism-based inactivator of CYP2D6. The generation of carbene intermediate might be mainly responsible for the enzyme inactivation.