Assessment of the inhibition risk of shikonin on cytochrome P450 via cocktail inhibition assay

Tang, Shuowen; Chen, Ang; Zhou, Xiaojing; Li, Zeng; Liu, Mingyao; Wang, Xin

doi:10.1016/j.toxlet.2017.09.014

Cited by 28 publications

(20 citation statements)

References 40 publications

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“…However, the relatively low Ki values of shikonin would have a high-risk potential to cause possible toxicity, especially drug–drug or food–drug interactions based on the potent inhibition of CYP enzymes (Tang et al. 2017). Hence, there has been increased interest in the potent shikonin derivatives with lower toxicity and stronger antitumour activities (Lin et al.…”

Section: Introductionmentioning

confidence: 99%

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway

Zhu

Zhong

Long³

et al. 2019

Pharmaceutical Biology

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Context: Shikonins, a series of natural occurring naphthoquinones extracted from Arnebia euchroma (Royle) Jonst. (Boraginaceae), have antitumor activities and low toxicity. Objective: To illuminate potential activity and mechanism of shikonins against colorectal cancer (CRC). Materials and methods: Five shikonins were isolated from A. euchroma , and elucidated by extensive spectroscopic analysis. Anti-proliferative activities of shikonins (0–100 μg/mL) on human colorectal cells were evaluated by MTT and CCK-8 for 24 or 48 h. Cell apoptosis and cycle distribution were examined by FCM analysis. The expression of PI3K/Akt/mTOR pathway mRNAs and proteins was analysed by RT-PCR and Western blot, respectively. Cell viability, cell apoptosis, cell cycle and protein expression were measured, when co-treated with PI3K/Akt/mTOR pathway inhibitors. The in vivo activity of deoxyshikonin was evaluated using xenograft tumour model. Results: Deoxyshikonin and another four shikonins were isolated and identified. Deoxyshikonin exhibited anti-proliferative activity with IC 50 of 10.97 μM against HT29 cells. Moreover, the percentage of early apoptotic cells and G0/G1 cells increased from 1 to 29% and 44 to 67% with 0–50 μg/mL deoxyshikonin, respectively. Deoxyshikonin also down-regulated the expression of PI3K, p-PI3K, Akt, p-Akt308 and mTOR proteins in HT29 and DLD-1 cells. Moreover, LY294002, NVP-BEZ235 and MK-2206 can make deoxyshikonin more cell proliferation inhibited, cell cycle arrested at G0/G1 and apoptosis promoted. In vivo study, the weight of tumour tissues at deoxyshikonin groups was significantly reduced compared with the control group, and PI3K, p-PI3K, Akt, p-Akt308 and mTOR expression was decreased. Discussion and conclusions: We can conclude that deoxyshikonin isolated from Arnebia euchroma inhibited CRC through the PI3K/Akt/mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway

Zhu

Zhong

Long³

et al. 2019

Pharmaceutical Biology

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“…For CYP inhibition assays, phenacetin, coumarin, paclitaxel, diclofenac, omeprazole, dextromethorphan, chlorzoxazone and testosterone were used as substrates for CYP1A, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. The substrate concentration was selected on the basis of the previously reported cocktail methods [ 18‐22 ] with very minor modifications. The final concentrations of the substrates and positive control inhibitors were listed in Tables 1 and 2.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo

Fang

Huang

Zhang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives This study aimed to evaluate the inhibitory effects of Huosu Yangwei oral liquid (HSYW) on cytochrome P450 enzymes (CYPs) and to investigate whether this herbal medicine could modulate the pharmacokinetic behaviour of the co-administered CYP-substrate drug apatinib. Methods Cytochrome P450 enzymes inhibition assays were conducted in human liver microsomes (HLM) by a LC-MS/MS method for simultaneous determination of the oxidative metabolites of eight probe substrates for hepatic CYPs. The modulatory effects of HSYW on the oxidative metabolism of apatinib were investigated in both HLM and rat liver microsomes (RLM). The influences of HSYW on the pharmacokinetic behaviour of apatinib were investigated in rats. Key findings Huosu Yangwei oral liquid inhibited all tested CYPs in human liver preparations, with the IC 50 values ranged from 0.3148 to 2.642 mg/ml. HSYW could also inhibit the formation of two major oxidative metabolites of apatinib in liver microsomes from both human and rat. In-vivo assays demonstrated that HSYW could significantly prolong the plasma half-life of apatinib by 7.4-fold and increase the AUC 0-inf (nMÁh) of apatinib by 43%, when HSYW (10 ml/kg) was co-administered with apatinib (10 mg/kg) in rats. Conclusions Huosu Yangwei oral liquid could inhibit mammalian CYPs and modulated the metabolic half-life of apatinib both in vitro and in vivo.

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“…cytochrome P450 (cYP450) enzymes are considered to be principal phase i drug-metabolizing enzymes involved in the biotransformation of ~90% of pharmaceutical drugs (1,2). The major cYPs include cYP1a, cYP2B, cYP2c, cYP2d, CYP2E and CYP3A (3).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

et al. 2019

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Ticagrelor and prasugrel are widely used in the treatment of acute coronary syndrome. The co-administration of ticagrelor or prasugrel with statins in the clinic has already drawn a great deal of attention. The aims of the present study were to evaluate the safety and effectiveness, and guide the rational clinical use of, co-administration of ticagrelor or prasugrel with statins by exploring potential drug interactions. The activity of cytochrome P450 family 3 subfamily a member 4 (cYP3a4) was detected, and its protein and mrna expression levels were measured in a rat model and liver microsomes to evaluate the effect of the drug combinations on cYP3a4. High performance liquid chromatography, western blotting and reverse transcription-quantitative Pcr were used to perform these investigations. The in vitro experiments suggested that ticagrelor inhibited cYP3a4 activity, with ic 50 and inhibitor constant (K i) values of 68.74 and 26.47 µM, respectively; prasugrel also inhibited cYP3a4, activity with ic 50 and K i values of 16.24 and 10.84 µM, respectively. When different dosages of the antagonists were combined with simvastatin or atorvastatin, the metabolic rate was reduced more effectively at higher dosages when compared with lower dosages. an in vivo pharmacokinetic study demonstrated that the co-administration of ticagrelor or prasugrel with simvastatin caused an increase in the principal pharmacokinetic parameters of the probe drug dapsone [area under the concentration/time curve (auc) 0-t , auc 0-∞ and t 1/2 ] and a decrease in clearance compared with ticagrelor, prasugrel or simvastatin alone. Additional studies confirmed that the two investigated P2Y12 inhibitors were able to decrease the protein level of cYP3a4 by promoting protein degradation through the proteasomal pathway, and combination with statins such as simvastatin had a synergistic inhibitory effect on cYP3a4 activity. These results demonstrated that the co-administration of P2Y12 inhibitors with simvastatin could markedly inhibit the activity of CYP3A4, and these findings will further influence the assessment of the clinical effectiveness (reduced or enhanced efficacy) and safety (bleeding and rhabdomyolysis) in the clinic.

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Assessment of the inhibition risk of shikonin on cytochrome P450 via cocktail inhibition assay

Cited by 28 publications

References 40 publications

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway

Deoxyshikonin isolated from Arnebia euchroma inhibits colorectal cancer by down-regulating the PI3K/Akt/mTOR pathway

Pharmacokinetic interaction between a Chinese herbal formula Huosu Yangwei oral liquid and apatinib in vitro and in vivo

Evaluation of cytochrome P450 3A4‑mediated drug‑drug interaction potential between P2Y12 inhibitors and statins

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