Identification of Quinone Methide Intermediate Resulting from Metabolic Activation of Icaritin <i>in Vitro</i> and <i>in Vivo</i>

Chen, Yan; Guo, Xiuping; Ma, Yufei; Hu, Xingjia; Peng, Ying; Zheng, Jiang

doi:10.1021/acs.chemrestox.8b00418

Cited by 15 publications

(11 citation statements)

References 14 publications

(24 reference statements)

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“…The fragment ion of m/z 306.0762 and 272.0885 was produced by glutathione moiety and cleavage of the cysteinyl C-S bond, respectively. The fragment ions observed from the glutathione moiety and cleavage of the cysteinyl C–S bond are the most typical ions found in glutathione conjugates [ 46 , 47 ]. The glutathione conjugate was also observed in the incubation samples with rCYP1A2, rCYP2C19, and rCYP2E1 ( Figure 5 ).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Ji¹,

Park²,

Bae³

et al. 2021

Pharmaceutics

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The stereoselectivity of the food drug inhibition potential of resveratrol on cytochrome P450s and uridine 5′-diphosphoglucuronosyl transferases was investigated in human liver microsomes. Resveratrol enantiomers showed stereoselective inhibition of CYP2C9, CYP3A, and UGT1A1. The inhibitions of CYP1A2, CYP2B6, and CYP2C19 by resveratrol were stereo-nonselective. The estimated Ki values determined for CYP1A2 were 13.8 and 9.2 μM for trans- and cis-resveratrol, respectively. Trans-resveratrol noncompetitively inhibited CYP3A and UGT1A1 activities with Ki values of 23.8 and 27.4 μM, respectively. Trans-resveratrol inhibited CYP1A2, CYP2C19, CYP2E1, and CYP3A in a time-dependent manner with Ki shift values >2.0, while cis-resveratrol time-dependently inhibited CYP2C19 and CYP2E1. The time-dependent inhibition of trans-resveratrol against CYP3A4, CYP2E1, CYP2C19, and CYP1A2 was elucidated using glutathione as a trapping reagent. This information helped the prediction of food drug interaction potentials between resveratrol and co-administered drugs which are mainly metabolized by UGT1A1, CYP1A2, CYP2C19, CYP2E1, and CYP3A.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Ji¹,

Park²,

Bae³

et al. 2021

Pharmaceutics

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“…Due to the strong covalent effect of isopentenyl, isopentenyl can induce toxicity of cells and mitochondria, leading to cell death . Moreover, the 4-position hydroxyl of Icaritin can cause the production of toxic quinone methide metabolites, which in turn induce liver toxicity . Therefore, we removed isopentenyl and 4-position hydroxyl groups and mainly focused on the optimization of the 2-position, 4-position, and 8-position of Icaritin in order to obtain new compounds with lower toxicity and higher efficiency.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Icaritin Derivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma Treatment

et al. 2021

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Icaritin is an active ingredient in Epimedium, which has a variety of pharmacological activities. However, the low activity of Icaritin and the unclear target greatly limit its application. Therefore, based on the structure of Icaritin, we adopted the strategy of replacing toxic groups and introducing active groups to design and synthesize a series of new analogues. The top compound C3 exhibited better antimultiple myeloma activity with an IC50 of 1.09 μM for RPMI 8226 cells, induced RPMI 8226 apoptosis, and blocked the cell cycle in the S phase. Importantly, transcriptome analysis, cellular thermal shift assay, and microscale thermophoresis assay confirmed that DEPTOR was the target of C3. Moreover, we explored its binding mode with C3. Especially, C3 displayed satisfactory inhibition of tumor growth in RPMI 8226 xenografts without obvious side effects. In summary, C3 was discovered as a novel putative inhibitor of DEPTOR for the treatment of multiple myeloma.

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“…To identify the existence of O-quinone metabolite which caused the enzyme inactivation, GSH was used as a trapping agent (Chen et al, 2019). ICT (60 μM), GSH (10 mM), HLM (1.0 mg/ml), MgCl 2 (4.0 mM), PBS (pH 7.4) and NADPH (1.0 mM) were mixed and incubated at 37℃ for 1 h. NADPH was not added in the negative control group.…”

Section: Role Of Human Gsts In the Inactivation Of Reactive O-quinone...mentioning

confidence: 99%

“…In addition, cancer patients are particularly susceptible to drug interactions due to the use of multiple medications and impaired physiological functions (Riechelmann et al, 2007;Conde-Estevez, 2017). Although the role of human P450 enzymes in ICT metabolism appears to be limited, one previous study showed that ICT can be bioactivated into quinone methide (QM) (Figure 1) intermediates by human CYP450 enzymes, which contribute to its adverse effects (Chen et al, 2019). The formation of electrophilic reactive intermediates, such as quinone and its tautomer, has been linked to P450 enzyme inactivation in various cases (Yang et al, 2018;Yadav et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Study of Icaritin-Induced Inactivation of Cytochrome P450 2C9

et al. 2023

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Icaritin (ICT) is a prenylflavonoid derivative that has been approved by NMPA for the treatment of hepatocellular carcinoma. This study aims to evaluate the potential inhibitory effect of ICT against cytochrome P450 enzymes and to elucidate the inactivation mechanisms. Results showed that ICT inactivated CYP2C9 in a time, concentration, and NADPH-dependent manner with K i = 1.896 μM, K inact = 0.02298 minutes -1 , and K inact /Ki = 12 minutes -1 mM -1 , whereas the activities of rest CYP isozymes was minimally affected. Additionally, the presence of CYP2C9 competitive inhibitor, sulfaphenazole, SOD/CAT system, and GSH all protected CYP2C9 from ICT-induced activity loss. Moreover, the activity loss was neither recovered by washing the ICT-CYP2C9 preincubation mixture nor the addition of potassium ferricyanide. These results, collectively, implied the underlying inactivation mechanism involved the covalent binding of ICT to the apoprotein and/or the prosthetic heme of CYP2C9. Furthermore, an ICT-quinone methide (QM)-derived GSH adduct was identified and human glutathione S-transferases (GST) isozymes GSTA1-1, GSTM1-1, and GSTP1-1 were shown to substantially involved in the detoxification of ICT-QM. Interestingly, our systematic molecular modeling work predicted that ICT-QM was covalently bind to C216, a cysteine residue located in the F-G loop downstream of substrate recognition site 2 (SRS2) in CYP2C9. The sequential molecular dynamics simulation confirmed the binding to C216 induced a conformational change in the active catalytic center of CYP2C9. Lastly, the potential risks of clinical drug-drug interactions triggered by ICT as a perpetrator were This article has not been copyedited and formatted. The final version may differ from this version.

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Identification of Quinone Methide Intermediate Resulting from Metabolic Activation of Icaritin in Vitro and in Vivo

Cited by 15 publications

References 14 publications

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Comprehensive Investigation of Stereoselective Food Drug Interaction Potential of Resveratrol on Nine P450 and Six UGT Isoforms in Human Liver Microsomes

Design, Synthesis, and Biological Evaluation of Icaritin Derivatives as Novel Putative DEPTOR Inhibitors for Multiple Myeloma Treatment

Mechanistic Study of Icaritin-Induced Inactivation of Cytochrome P450 2C9

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