Nitidine Chloride-Induced CYP1 Enzyme Inhibition and Alteration of Estradiol Metabolism.

Author(s) Mao, X.; Wang, J.; Wang, Q.; Yang, L.; Li, Y.Lin; Lin, H.; Peng, Y.; Zheng, J.
Journal Drug Metab Dispos
Date Published 2019 May 30
Abstract

Cytochrome P450 (CYPs) 1 family is an important phase Ⅰ enzyme involved in carcinogen activation. Nitidine chloride (NC) is a pharmacologically active alkaloid with polyaromatic hydrocarbon found in the roots of (Roxb.) DC, a traditional medicinal herb widely used in China. We examined the inhibitory effects of NC on CYPs1A1, 1B1, and 1A2. NC significantly inhibited CYPs1A1 and 1B1-catalyzed ethoxyresorufin -deethylation (EROD) activity (IC = 0.28 ± 0.06 and 0.32 ± 0.02 M, respectively) in a concentration-dependent manner, but only showed slight inhibition of CYP1A2 activity (IC > 50 M). Kinetic analysis revealed that NC competitively inhibited CYP1B1 with K of 0.47 ± 0.05 M, whereas NC caused a mixed type of inhibition on CYP1A1 with K and K of 0.14 ± 0.04 and 0.19 ± 0.09 M, respectively. The observed enzyme inhibition neither required NADPH nor revealed time dependency. Molecular docking manifested the generation of strong hydrogen-bonding interactions of Ser116 of CYP1A1 and Ser127 of CYP1B1 with methoxy moiety of NC. Additionally, NC-induced alteration of estradiol (E2) metabolism was also investigated in the present study. Hydroxyestradiols, including 2-hydroxyestradiol (nontoxic) and 4-hydroxyestradiol (genotoxic) generated in recombinant enzyme incubation systems and cultured MCF-7 cells were analyzed, and NC was found to preferentially inhibit the nontoxic 2-hydroxylation activity of E2 mediated by CYP1A1. In conclusion, NC was a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. The remarkable inhibition on E2 2-hydroxylation might increase the risk of 4-OHE2-induced genotoxicity. SIGNIFICANCE STATEMENT: CYP1 enzymes catalyze oxidative metabolism of a variety of compounds and are known to play a crucial role in the development of cancer. CYP1A1 and CYP1A2 are responsible for hydroxylation of estradiol (E2) at C-2 position, resulting in the formation of 2-hydroxyestradiol (2-OHE2), which is proposed to be a detoxification pathway. However, CYP1B1-mediated hydroxylation of E2 at C-4 position has been suggested to be a tumor initiator. The present study found that nitidine chloride (NC) is a mixed type inhibitor of CYP1A1 and a competitive inhibitor of CYP1B1. NC preferentially inhibited the nontoxic E2 2-hydroxylation pathway mediated by CYP1A1, which might increase the risk of 4-OHE2-induced genotoxicity and cause severe drug-drug interactions.

DOI 10.1124/dmd.119.086892
ISSN 1521-009X
Citation Mao X, Wang J, Wang Q, Yang L, Li YL, Lin H, et al. Nitidine Chloride-Induced CYP1 Enzyme Inhibition and Alteration of Estradiol Metabolism. Drug Metab Dispos. 2019.

Related Applications, Forms & Industries