Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes.

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Citation

Ma Z, Shi X, Zhang G, Guo F, Shan L, Cai J

Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes.

Evid Based Complement Alternat Med. 2016;2016:5416509. doi: 10.1155/2016/5416509. Epub 2016 Mar 10.

PubMed ID
27034690 [ View in PubMed
]
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 muM for CYP3A4 and 27.82 muM for CYP1A2. The values of inhibition kinetic parameters (Ki) were 21.15 muM and 2.22 muM 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 muM, 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 pi-pi 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
DiclofenacCytochrome P450 1A2ProteinHumans
Unknown
Substrate
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