Park, Eun-Ji Park, Keun wan Durai, Prasannavenkatesh Kim, Ki-Young Park, So-Young Kwon, Jaeyoung Lee, Hee Ju PAN, CHEOL HO Liu, Kwang-Hyeon 2024-01-12T02:34:13Z 2024-01-12T02:34:13Z 2022-12-02 2022-12 1999-4923 https://pubs.kist.re.kr/handle/201004/75887 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 ？M in a competitive inhibitory manner in HLMs, whereas it exhibited negligible inhibitory effect against other P450s (IC50 > 28.6 ？M). Obtusifolin also inhibited CYP1A1- and CYP1A2-mediated POD and ethoxyresorufin O-deethylation with IC50 values of <0.57 ？M when using recombinant enzymes. Our molecular docking models suggested that the high CYP1A2 inhibitory activity of obtusifolin may be attributed to the combination of hydrophobic interactions and hydrogen bonding. This is the first report of selective and potent inhibitory effects of obtusifolin against CYP1A, indicating their potential chemopreventive effects. English Multidisciplinary Digital Publishing Institute (MDPI) Potent and Selective Inhibition of CYP1A2 Enzyme by Obtusifolin and Its Chemopreventive Effects Article 10.3390/pharmaceutics14122683 1 Pharmaceutics, v.14, no.12, pp.2683 Pharmaceutics 14 12 2683 Y scie scopus 000902859400001 Pharmacology & Pharmacy Pharmacology & Pharmacy Article POLYCYCLIC AROMATIC-HYDROCARBONS CYTOCHROMES P450 1A1 ANTHRAQUINONES SPECTROMETRY VALIDATION ACTIVATION PLASMA SEMEN SEEDS RHEIN obtusifolin Cassiae semen chemoprevention inhibition