Nitidine Chloride Is a Mechanism-Based Inactivator of CYP2D6

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Xu MaoJiang Zheng

Abstract

Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. Several reports have revealed NC's 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 a 15-minute incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4.36 μM, kinact of 0.052 minute-1, and a 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(s) 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 ...Continue Reading

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Citations

Nov 30, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yan ChenJiang Zheng
May 31, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xu MaoJiang Zheng
Aug 27, 2019·Drug Metabolism Reviews·Bo Wen, Peter Gorycki
Oct 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Seung Wan SonJong Kook Park
Jul 28, 2021·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chen SunJiang Zheng

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