Identification of cytochrome P450 isoforms involved in the metabolism of artocarpin and assessment of its drug–drug interaction

Abstract

Artocarpin isolated from an agricultural plant Artocarpus communis has shows anti-inflammation and anticancer activities. In this study, we utilized recombinant human UDP-glucuronosyltransferasesupersomes (UGTs) and human liver microsomes to explore its inhibitory effect on UGTs and cytochrome p450 enzymes (CYPs). Chemical inhibition studies and screening assays with recombinant human CYPs were used to identify if CYP isoform is involved in artocarpin metabolism. Artocarpin showed strong inhibition against UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, CYP2C8 and CYP3A4. In particular, artocarpin exhibited competitive inhibition against CYP3A4 and noncompetitive inhibition against UGT1A3 and UGT1A7. The half inhibition concentration values for CYP3A4, UGT1A3 and UGT1A7 were 4.67, 3.82 and 4.82 μm, and the inhibition kinetic parameters for them were 0.78, 2.67 and 3.14 μm, respectively. After artocarpin was incubated in human liver microsomes and determined by HPLC, we observed its main metabolites (M1 and M2). In addition, we proved that CYP2D6 played the key role in the biotransformation of artocarpin in human liver microsomes. The result of molecular docking further confirmed that artocarpin interacted with CYP2D6, CYP2C8 and CYP3A4 through hydrogen bonds. This study provided preliminary results for further research on artocarpin or artocarpin-containing herbs.

An In Vitro Study for Evaluating Permeability and Metabolism of Kurarinone

“…RLMs were used to assess the inhibitory effects of kurarinone (100 μ M) on six different human isoforms (CYP1A2, CYP2C9, CYP2D6, CYP2E1, CYP3A4, and CYP2C19). The probe substrates used in this experiment were 40 μ M phenacetin for CYP1A2, 10 μ M diclofenac for CYP2C9, 25 μ M dextromethorphan for CYP2D6, 120 μ M chlorzoxazone for CYP2E1, 35 μ M testosterone for CYP3A4, and 20 μ M ( S )-mephenytoin for CYP2C9 as described earlier [ 27 ]. The reaction system has been described in Section 2.3 .…”

Identification of the cytochrome P450 enzymes involved in the oxidative metabolism of trantinterol using ultra high-performance liquid chromatography coupled with tandem mass spectrometry

“…5 Moreover, CYPs can be inhibited or induced during concomitant medical treatment, which have been recognized as an important cause of many drug-drug interactions (DDIs), resulting in a lot of drug adverse events. [6][7][8][9][10] In the past few years, a number of drugs have been withdraw from the market because of this reason. 11,12 Thus, the in vitro identication of drug metabolizing CYPs will help develop better therapeutic strategies with regard to the prediction of possible drug-drug interactions during drug treatment, which can sufficiently improve the efficacy and reduce the toxicity.…”