XENOBIOTICA
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2026
·
IF 1.5
Jia-ou Chen,Ling-li Zhou,Jian-heng Lin,Hao-tian Zhou,Lai-fang Sun,Cheng-ke Huang
1. This study aims to investigate the effects of orally administered paeoniflorin (PF), a major bioactive compound from Paeonia lactiflora, on cytochrome P450 (CYP450) enzyme activity in rats to assess potential drug-drug interactions (DDIs). Following PF treatment, rats received a mixed probe drug solution containing phenacetin (PHE), tolbutamide (TOL), omeprazole, and metoprolol, and plasma concentrations of the substrates and metabolites were quantified using ultra-high-performance liquid chromatography-tandem mass spectrometry. The metabolic ratio, calculated as the ratio of metabolite to parent drug area under the curve (AUC), was used to evaluate CYP activity.2. Results showed that AUCAcetaminophen/AUCPHE values were significantly elevated in PF-treated groups, indicating induction of CYP1A2, whereas AUCOHTOL/AUCTOL values were significantly reduced, suggesting inhibition of CYP2C11. No significant effects were observed on CYP2C or CYP2D2 activities.3. These findings indicate that PF can modulate CYP1A2 and CYP2C11 activities under the experimental conditions tested, as assessed using PHE and TOL as functional markers. However, the magnitude of these effects was modest and observed only at relatively high PF doses (50 and 100 mg/kg). Given the inherent species differences between rat and human CYP enzymes, direct extrapolation of these findings to human CYP1A2 and CYP2C11 requires further validation in human-relevant models.
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RSC Advances
·
2026
·Vol. 16
·期 14
·12570-12578
·
IF 6.1
Hang Yin,Lei Zhu,Xiaoyu Wang,Zhen Wang,Hecheng Wang,Yong Liu
As a natural plant active ingredient, sesamin has the following nutritional values: anti-inflammatory, antioxidant, anti-hypertension, liver protection, and cholesterol reduction, and has been developed for dietary supplements to assist clinical drug therapy. However, it is not known whether it inhibits the catalytic activities of drug-metabolizing enzymes. Hence, the objective of this research was to assess the inhibitory effects of sesamin on cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) and to predict the risk of inducing food–drug interactions (FDIs). The results indicated that sesamin had no significant inhibitory effects on UGTs. However, since people may take sesame in excessive amounts, the FDIs mediated by UGTs still cannot be ignored. Sesamin could increase the potential risk of FDIs by inhibiting the activities of CYP2C9 and CYP2C19. It is worth noting that for phenytoin, a CYP2C9 substrate with a narrow therapeutic window, sesamin can significantly inhibit the formation of its hydroxylation products and cause clinically significant FDIs. Therefore, when patients are being treated with CYP2C9 and CYP2C19 substrate drugs with narrow therapeutic windows, high doses of sesame or other sesamin-rich substances should be avoided.
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Frontiers in Pharmacology
·
2023
·
IF 5.6
Li Yingzi,Liu Xiaoyan,Li Ludi,Zhang Tao,Gao Yadong,Zeng Kewu,Wang Qi
Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.
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Foods
·
2023
·Vol. 12
·期 3
·539
·
IF 5.2
Zixian He,Zhiwei Liu,Haihuan Xie,Pengjie Luo,Xiangmei Li
Herein, an ultrasensitive lateral flow immunoassay (LFIA), based on metal-organic framework-decorated polydopamine (PCN-224@PDA) was first established to detect multiple sulfonylureas (SUs) in functional foods. The PCN-224@PDA was synthesized using the one-pot hydrothermal method and covalently coupled with SUs antibodies, and the coupling rate was up to 91.8%. The detection limits of the developed PCN-224@PDA-LFIA for multiple SUs in functional teas and capsules were 0.22–3.72 μg/kg and 0.40–3.71 μg/kg, and quantification limits were 0.75–8.19 μg/kg and 1.03–9.08 μg/kg, respectively. The analytical sensitivity was 128-fold higher than that of similar methods reported so far. The recovery rates ranged from 83.8 to 119.0%, with coefficients of variation of 7.6–14.4%. The parallel analysis of 20 real samples by LC-MS/MS confirmed the reliability of the proposed method. Therefore, our work offers novel, ultrasensitive, and rapid technical support for on-site monitoring of SUs in functional foods.Keywords:sulfonylureas;metal-organic frameworks;polydopamine;lateral flow immunoassay;functional foods
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PHARMACEUTICAL BIOLOGY
·
2023
·
IF 3.8
Jianzhong Wu,Zhen Zhang,Qimei Wu,Linli Zhang,Zhipeng Chen,Hairong Zhao,Xiumei Wu,Yu Zhao,Chenggui Zhang,Jian Ge,Heng Liu
Context Periplaneta americana L. (Blattariae) is used as a treatment for ulcerative colitis (UC) in Chinese traditional medicine.Objective To evaluate the antioxidative activity of P. americana whole body ethanol extract (PAE) on UC mice and whether glycine and proline could be used for quality control and identification of active PAE components.Materials and methods NCM460 cells were pre-incubated in PAE, AA-L, AA-M, and AA-H (low, high and medium doses of proline and glycine), then treated with recombinant human TNF-α. The glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) and reactive oxygen (ROS) levels were determined. UC mice were fed with water containing 2.5% dextran sulfate sodium (w/v) after pre-treatment with different doses of PAE once a day for 7 days. ELISA was used to detect the concentrations of inflammation-related factors. Colon tissues of mice were used to detect the activity of myeloperoxidase (MPO), GSH, MDA, and SOD. Histological changes were observed using H&E staining. The expression of target proteins was determined by western blotting.Results In vivo, PAE treatment reduced the DAI score more than in the model group, restoring the weight and colonic length. It also reduced the severity of colitis, and inflammatory and oxidative stress intensity. Additionally, western blotting showed that the Nrf2 pathway was activated by PAE. In vitro PAE significantly alleviated TNF-α-induced cell damage and oxidative stress, which is relevant to the activation of the Nrf2 pathway.Conclusions PAE may relieve oxidative stress through the Nrf2 signaling pathway, and proline and glycine may be used as active components of its antioxidative stress activity.
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CHEMICO-BIOLOGICAL INTERACTIONS
·
2022
·
IF 5.168
Xu Wang,Lingwen Dong,Guode Zhao,Weiwei Li,Ying Peng,Jiang Zheng
2,3,5,4′-Tetrahydroxy stilbene-2-Ο- β -D-glucoside (TSG) and emodin (EMD) are two main components of Polygonum multiflorum Thunb. (PMT). Its root is widely used as herbal medicine and supplement. However, PMT-induced liver injury has drawn increasing attention. The purpose of this study was to investigate the interaction of TSG with EMD in the aspects of enzymology , pharmacokinetics , and hepatotoxicity. Co-administration with TSG increased internal exposure of EMD, EMD-derived hepatic protein adduction, and EMD-induced liver injury in mice. Mouse and human liver microsomal incubation study demonstrated that co-incubation with TSG decreased the formation of hydroxylation metabolites of EMD. Human recombinant cytochrome P450 enzyme incubation study showed that TSG induced time-, concentration-, NADPH-dependent and irreversible inhibition of CYP2C19 and CYP3A4 . An epoxide metabolite derived from TSG was responsible for the observed enzyme inactivations. The findings allow us to better understand the mechanisms by which herbal processing detoxifies raw PMT.
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FOOD CHEMISTRY
·
2022
·
IF 9.231
Xiaoli Guo,Tingze Ren,Jianchun Ji,Yan Yang,Xin Di
In this work, a combination of QuEChERS and dispersive micro-solid phase extraction (D-μ-SPE) based on dissolvable layered double hydroxide (LDH) has been established for preconcentration and enrichment of sulfonylurea herbicides (SUHs) in wolfberry samples. The QuEChERS was used for extraction and purification of SUHs, followed by D-μ-SPE for further enrichment of targeted analytes to obtain superior extraction performance. Dissolvable LDH nanosheets were used as absorbents, thus eliminating the elution step needed in traditional D-μ-SPE. The main influence experimental variables including pH of sample solution, amount of LDH, vortex time and volume of acidic solution were optimized in detail. Under the optimized conditions, the proposed method shows high precision (RSDs < 12 .7%), low limits of detection (0.01–0.5 ng/g) and limits of quantitation (0.1–2.0 ng/g), acceptable recovery (80.1%–97.1%), thus making it a good alternative analytical strategy for the determination of SUHs residues at the low nanogram per gram range with desirable sensitivity.
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XENOBIOTICA
·
2021
·
IF 1.908
Jadera Talap,Zhuowei Shen,Jing Nie,Jie Pan,Mingcheng Xu,Kui Zeng,Kaifeng He,Fengting Ou,Houhong He,Jianbiao Yao,Ruwei Wang,Lushan Yu,Su Zeng
6-Hydroxykynurenic acid (6-HKA) is a nitrogen-containing phenolic acid compound in Ginkgo biloba leaves. The pharmacological activities of 6-HKA have been reported and shown that 6-HKA has the potential to become a therapeutic drug and may play an important role in the treatment of nervous system diseases. However, there are few studies on the drug metabolism and transport of 6-HKA. The aim of this study is to investigate the in vitro metabolism of 6-HKA and its interaction with multiple important drug transporters.The in vitro metabolism experiments in the present study demonstrate that 6-HKA might not undergo phase-I or phase-II metabolism in hepatic microsomes/S9 of rats. In addition, some drug transporters, including OAT1/3, OCT2, MDR1, OATP1B1, MATE1/2K and OCTN2, were investigated. The cellular uptake assays indicate that 6-HKA exhibits inhibition to the transport of classical substrates mediated by OAT3, OCT2, MATE2K and OCTN2 but has no significant effect on the transport of substrates mediated by MDR1, OAT1, OATP1B1 or MATE1. Further investigation of cellular accumulation assays shows that 6-HKA might be the substrate of OAT3, but not OCT2 or OCTN2. The bidirectional transport study suggests that 6-HKA is not a substrate of MDR1.The information about the in vitro metabolism of 6-HKA and the interaction between 6-HKA and some transporters will help us to better understand the pharmacokinetic properties of 6-HKA and provide reference for its pharmacodynamics, DDIs and drug-food interactions studies.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 3.534
Zifei Qin,Peile Wang,Shuyi Duan,Xiaoying Wan,Han Xing,Jing Yang,Xiaojian Zhang,Zhihong Yao,Xinsheng Yao
Isobavachalcone, a naturally occurring chalcone in Psoralea corylifolia , posses many biological properties including anticancer, antiplatelet, and antifungal. However, its glucuronidation, glucuronides excretion, and drug-drug interaction (DDI) involving in human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT) enzymes, and efflux transporters (BCRP and MRPs) remains unclear so far. After incubation, three glucuronides were produced by HLM and HIM with total intrinsic clearance ( CL int ) of 236.71 and 323.40 μL/min/mg, respectively. Reaction phenotyping proved UGT1A1, 1A3, 1A7, 1A8, and 1A9 played important roles in glucuronidation with total CL int values of 62.69–143.00 μL/min/mg. Activity correlation analysis indicated UGT1A1 and UGT1A3 participated more in the glucuronidation. In addition, the glucuronidation showed marked species differences, and rabbits and dogs were probably appropriate model animals to investigate the in vivo glucuronidation. Furthermore, BCRP , MRP1, and MRP4 transporters were identified as the most important contributors to glucuronides excretion in HeLa1A1 cells based on gene silencing method. Moreover, isobavachalcone demonstrated broad-spectrum inhibitory effects against CYP2B6 , CYP2C9 , CYP2C19 , CYP2D6 , CYP2E1 , UGT1A1, UGT1A9, UGT2B7 with IC 50 values of 1.08–9.78 μM. Except CYP2B6 and CYP2D6, the calculated [I]/ K i values for other enzymes were all greater than 0.1, indicating the inhibition of systemic metabolism or elimination for these enzyme substrates seems likely. Taken together, we summarized metabolic fates of isobavachalcone including glucuronidation and efflux transport as well as inhibitory effects involving in human CYP and UGT enzymes.
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FOOD AND CHEMICAL TOXICOLOGY
·
2021
·
IF 6.025
Ying Liu,Shiyu Zhang,Tingting Jiang,Rong Tan,Yao Fu,Xiaojing Yang,Bowen Gong,Ying Zou,Weiwei Li,Jiang Zheng
Bergamottin (BGM) is a major furanocoumarin constituent of grapefruit and is reported to have inhibitory effects on cytochrome P450 enzymes. This study investigated the chemical interactions between BGM and the enzyme CYP2C9 . BGM exhibited time-, concentration-, and NADPH-dependent inhibition of CYP2C9. Co-incubation with diclofenac, a reversible inhibitor of CYP2C9, attenuated the time-dependent enzyme inhibition. Exhaustive dialysis did not restore enzyme activity post-inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse BGM-induced CYP2C9 inactivation. A GSH trapping study suggested that BGM was metabolized to an epoxide and/or γ-ketoenal that may have been responsible for the enzyme inactivation. In conclusion, BGM can be characterized as a mechanism-based inactivator of CYP2C9 acting via the formation of an epoxide and/or γ-ketoenal.
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RSC Advances
·
2020
·Vol. 10
·期 58
·35141-35152
·
IF 3.119
Xinqiang Li,Han Xing,Zifei Qin,Jing Yang,Peile Wang,Xiaojian Zhang,Zhihong Yao,Xinsheng Yao
Bavachinin, a natural bioactive flavanone, is reported to have many pharmacological proprieties, especially anti-osteoporosis activity. Here we aim to determine the roles of cytochrome P450s (CYP), UDP-glucuronosyltransferases (UGT), and efflux transporters in metabolism and drug–drug interactions (DDI) of bavachinin. Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM) and human intestine microsomes (HIM). Reaction phenotyping was used to identify the main CYPs and UGTs. Gene silencing methods were employed to investigate the roles of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa1A1 cells. Inhibition mechanisms towards CYPs and UGTs were explored through kinetic modeling. Three phase I metabolites (M1–M3) and one glucuronide (G1) were detected after incubation of bavachinin with HLM and HIM. The intrinsic clearance (CLint) values of M1 and G1 by HLM were 89.4 and 270.2 μL min−1 mg−1, respectively, while those of M3 and G1 by HIM were 25.8 and 247.1 μL min−1 mg−1, respectively. CYP1A1, 1A2, 1B1, 2C8, 2C19, and UGT1A1, 1A8 participated more in bavachinin metabolism. The metabolism showed marked species difference. BCRP and MRP4 were identified as the main contributors. Bavachinin displayed potent inhibitory effects against several CYP and UGT isozymes (Ki = 0.28–2.53 μM). Bavachinin was subjected to undergo metabolism and disposition by CYPs, UGTs, BCRP, MRP4, and was also a potent non-selective inhibitor against several CYPs and UGTs.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2020
·Vol. 72
·期 12
·1865-1878
·
IF 2.571
Xing Han,Yang Jing,Ren Kaidi,Qin Zifei,Wang Peile,Zhang Xiaojian,Yao Zhihong,Gonzalez Frank J,Yao Xinsheng
ObjectivesIsobavachin is a phenolic with anti-osteoporosis activity. This study aimed to explore its metabolic fates in vivo and in vitro, and to investigate the potential drug–drug interactions involving CYPs and UGTs.MethodsMetabolites of isobavachin in mice were first identified and characterized. Oxidation and glucuronidation study were performed using liver and intestine microsomes. Reaction phenotyping, activity correlation analysis and relative activity factor approaches were employed to identify the main CYPs and UGTs involved in isobavachin metabolism. Through kinetic modelling, inhibition mechanisms towards CYPs and UGTs were also explored.Key findingsTwo glucuronides (G1 - G2) and three oxidated metabolites (M1 - M3) were identified in mice. Additionally, isobavachin underwent efficient oxidation and glucuronidation by human liver microsomes and HIM with CLint values from 5.53 to 148.79 μl/min per mg. CYP1A2, 2C19 contributed 11.3% and 17.1% to hepatic metabolism of isobavachin, respectively, with CLint values from 8.75 to 77.33 μl/min per mg. UGT1As displayed CLint values from 10.73 to 202.62 μl/min per mg for glucuronidation. Besides, significant correlation analysis also proved that CYP1A2, 2C19 and UGT1A1, 1A9 were main contributors for the metabolism of isobavachin. Furthermore, mice may be the appropriate animal model for predicting its metabolism in human. Moreover, isobavachin exhibited broad inhibition against CYP2B6, 2C9, 2C19, UGT1A1, 1A9, 2B7 with Ki values from 0.05 to 3.05 μm.ConclusionsCYP1A2, 2C19 and UGT1As play an important role in isobavachin metabolism. Isobavachin demonstrated broad-spectrum inhibition of CYPs and UGTs.
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