Potent and Selective Inhibition of CYP1A2 Enzyme by Obtusifolin and Its Chemopreventive Effects

Autor: Eun-Ji Park, Keunwan Park, Prasannavenkatesh Durai, Ki-Young Kim, So-Young Park, Jaeyoung Kwon, Hee Ju Lee, Cheol-Ho Pan, Kwang-Hyeon Liu
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Pharmaceutics, Vol 14, Iss 12, p 2683 (2022)
Druh dokumentu: article
ISSN: 1999-4923
DOI: 10.3390/pharmaceutics14122683
Popis: Obtusifolin, a major anthraquinone component present in the seeds of Cassia tora, exhibits several biological activities, including the amelioration of memory impairment, prevention of breast cancer metastasis, and reduction of cartilage damage in osteoarthritis. We aimed to evaluate the inhibitory effects of obtusifolin and its analogs on CYP1A enzymes, which are responsible for activating procarcinogens, and investigate its inhibitory mechanism and chemopreventive effects. P450-selective substrates were incubated with human liver microsomes (HLMs) or recombinant CYP1A1 and CYP1A2 in the presence of obtusifolin and its four analogs. After incubation, the samples were analyzed using liquid chromatography-tandem mass spectrometry. Molecular docking simulations were performed using the crystal structure of CYP1A2 to identify the critical interactions between anthraquinones and human CYP1A2. Obtusifolin potently and selectively inhibited CYP1A2-mediated phenacetin O-deethylation (POD) with a Ki value of 0.031 µM in a competitive inhibitory manner in HLMs, whereas it exhibited negligible inhibitory effect against other P450s (IC50 > 28.6 µM). Obtusifolin also inhibited CYP1A1- and CYP1A2-mediated POD and ethoxyresorufin O-deethylation with IC50 values of
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje