Metabolism and Metabolic Inhibition of Xanthotoxol in Human Liver Microsomes.

Zhongnv Ma,Xianbao Shi,Gang Zhang,Lina Shan,Feng Guo,Jiqun Cai

doi:10.1155/2016/5416509

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 (CLH) and the CLH value was 15.91 mL·min−1·kg−1 body weight. These data were significant for the application of xanthotoxol and xanthotoxol-containing herbs.

Highlights

Xanthotoxol (Figure 1), a biologically active linear furocoumarin, occurs in a large number of plants and is mainly extracted from the fruit of Fructus Cnidii [1]
We examined the inhibitory potential of xanthotoxol on cytochrome P450 (CYP450) and kinetic parameters using in vitro human liver microsomes (HLMs), which will provide the basis for further in vivo studies in future
Cytochrome P450 enzymes (CYP450s) are heme-thiolate proteins that are responsible for the oxidative metabolism of numerous xenobiotics as well as endogenous substrates [15]

Summary

Introduction

Xanthotoxol (Figure 1), a biologically active linear furocoumarin, occurs in a large number of plants and is mainly extracted from the fruit of Fructus Cnidii [1]. Xanthotoxol shows strong pharmacological activities as antiinflammatory, antioxidant, 5-HT antagonistic, and neuroprotective effects [2,3,4]. Respecting so many pharmacological activities of xanthotoxol, xanthotoxol is likely used with other drugs, and the possibility of herb-induced toxicity should be paid more attention. Among all of the metabolic processes, metabolisms catalyzed by the cytochrome P450 (CYP450) enzymes are the most important because almost 70%–80% of the known Phase I metabolisms are attributed to them [5]. In recent years, using humanized enzyme to study the drugdrug interactions in vitro has avoided the species differences of enzyme’s isoforms, expression, and activities [8, 9]. The US FDA has already confirmed the validity of in vitro enzymes to assess the in vivo interaction between medications [10, 11]

Methods

Results

Conclusion