title: Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes.
abstract: Cytochrome p450 (CYP450) enzymes are predominantly involved in Phase I metabolism of xenobiotics. In this study, the CYP450 isoforms involved in xanthotoxol metabolism were identified using recombinant CYP450s. In addition, the inhibitory effects of xanthotoxol on eight CYP450 isoforms and its pharmacokinetic parameters were determined using human liver microsomes. CYP1A2, one of CYP450s, played a key role in the metabolism of xanthotoxol compared to other CYP450s. Xanthotoxol showed stronger inhibition on CYP3A4 and CYP1A2 compared to other isoenzymes with the IC50 of 7.43 μM for CYP3A4 and 27.82 μM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 μM and 2.22 μM for CYP1A2 and CYP3A4, respectively. The metabolism of xanthotoxol obeyed the typical monophasic Michaelis-Menten kinetics and V max, K m , and CLint values were calculated as 0.55 nmol·min(-1)·mg(-1), 8.46 μM, and 0.06 mL·min(-1)·mg(-1). In addition, the results of molecular docking showed that xanthotoxol was bound to CYP1A2 with hydrophobic and π-π bond and CYP3A4 with hydrogen and hydrophobic bond. We predicted the hepatic clearance (CL H ) and the CL H value was 15.91 mL·min(-1)·kg(-1) body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs.
authors.affiliation: Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110001, China.
authors.forename: Zhongnv
authors.identifier: 0000-0002-4338-9920
authors.initials: Z
authors.lastname: Ma
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Xianbao
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110001, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001, China.
authors.forename: Lina
authors.identifier: 0000-0003-1187-9156
authors.initials: L
authors.lastname: Shan
authors.affiliation: Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang 110001, China.
authors.forename: Jiqun
authors.identifier: 0000-0003-4652-1306
authors.initials: J
authors.lastname: Cai