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Corydaline is a bioactive alkaloid with various antiacetylcholinesterase, antiallergic, and antinociceptive activities found in the medicinal herb Corydalis Tubers. The inhibitory potential of corydaline on the activities of seven major human cytochrome P450 and four UDP-glucuronosyltransferase enzymes in human liver microsomes was investigated usi...
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Context 1
... tubers, the roots of Corydalis yanhusuo W.T. Wang, have long been used as an herbal drug for their analgesic and anti-ulcer effects [1][2][3]. Corydaline, 2,3,9,10-tetramethoxy-13-methyl- 5,8,13,13a-tetrahydro-6H-isoquino[3,2-a]isoquinoline (Figure 1), is isolated from Corydalis tubers and has been demonstrated to show antiacetylcholinesterase [4][5][6] and antibutylcholinesterase activity [4], antiallergic activity [7], and antinociceptive activity [8]. Corydaline also promotes gastric emptying and facilitates gastric accommodation [9]. Use of herbal medicine and botanical drugs to prevent common illness is on the rise among the global population [10]. Because botanical drugs share the same metabolic and transport proteins, including cytochrome P450 (CYP) enzymes, UDP-glucuronosyltransferase (UGT) enzymes, and drug transporters, such as P-glycoprotein, with commonly used drugs, the potential for herb-drug interactions is substantial [11]. Several medicinal herbs, including garlic (Allium sativum), ginkgo (Ginko biloba), ginseng (Panax ginseng), milk thistle (Silybum marianum), licorice (Glycyrrhiza glabra), and St. John's wort (Hypericum perforatum), have been reported to cause such herb-drug interactions [12][13][14]. Therefore, interactions among therapeutic drugs, as well as interactions of drugs with food and herbal medications, have attracted considerable attention ...
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Citations
... The inhibitory effects of other natural compounds on UGT1A190,93,101,[118][119][120][121][122][123] . ...
... The inhibitory effects of other natural compounds on UGT1A190,93,101,[118][119][120][121][122][123] . ...
Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1–ligand interactions. © 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences
... The metabolic investigation benefits the understanding of corynoline-prompted cytotoxicity and CYP inhibition. In HLMs, the CYP2C19-mediated S-mephenytoin-4ʹ-hydroxylatoin and CYP2C9-mediated diclofenac 4-hydroxylation were inhibited by CDL [68]. CDL also suppressed the CYP3Amediated midazolam hydroxylation in a dose-dependent mode. ...
... In HLMs, UGT1A1 and 1A9 were modestly inhibited by CDL [68]. UGT1A1 was marginally inhibited by the Corydalis-containing DA-9701 and Corydalis tuber extract [69]. ...
Although investigations in metabolism and pharmacokinetics of Ranunculales phytometabolites are booming, data obtained from human and animal studies have not been summarized as a whole to outline current trends and to predict future development.
AREAS COVERED:
Here, we highlight the current knowledge, as well as the challenges around the DMPK (drug metabolism and pharmacokinetics) associated concerns in streamlining drug research and therapeutic use of Ranunculales phytometabolites. Data from various in vivo and in vitro models are classified and discussed. DMPK characteristics of Ranunculales phytometabolites are summarized and presented according to the phylogenetic relationship of families and genera. This review also presents an overview of the complex interaction between drug metabolizing enzymes/transporters and phytochemicals, as well as of the most advanced approaches in the relevant field.
EXPERT OPINION:
Since species-specific differences in DMPK exist, data obtained from animal studies may not be sufficient to predict drug metabolism reactions in humans. Omics-based methodologies (genomics, epigenomics, transcriptomics, proteomics, microbiomics, and metabolomics) should be used to enhance the reliability of DMPK prediction. The fluorescent probes may bridge the gap between conventional models and in vivo clinical studies in humans and provide a consistent basis for DMPK assay development.
... The metabolic investigation benefits the understanding of corynoline-prompted cytotoxicity and CYP inhibition. In HLMs, the CYP2C19-mediated S-mephenytoin-4ʹ-hydroxylatoin and CYP2C9-mediated diclofenac 4-hydroxylation were inhibited by CDL [68]. CDL also suppressed the CYP3Amediated midazolam hydroxylation in a dose-dependent mode. ...
... In HLMs, UGT1A1 and 1A9 were modestly inhibited by CDL [68]. UGT1A1 was marginally inhibited by the Corydalis-containing DA-9701 and Corydalis tuber extract [69]. ...
Introduction:
Although investigations in metabolism and pharmacokinetics of Ranunculales phytometabolites are booming, data obtained from human and animal studies have not been summarized as a whole to outline current trends and to predict future development.
Areas covered:
Here, we highlight the current knowledge, as well as the challenges around the DMPK (drug metabolism and pharmacokinetics) associated concerns in streamlining drug research and therapeutic use of Ranunculales phytometabolites. Data from various in vivo and in vitro models are classified and discussed. DMPK characteristics of Ranunculales phytometabolites are summarized and presented according to the phylogenetic relationship of families and genera. This review also presents an overview of the complex interaction between drug metabolizing enzymes/transporters and phytochemicals, as well as of the most advanced approaches in the relevant field.
Expert opinion:
Since species-specific differences in DMPK exist, data obtained from animal studies may not be sufficient to predict drug metabolism reactions in humans. Omics-based methodologies (genomics, epigenomics, transcriptomics, proteomics, microbiomics, and metabolomics) should be used to enhance the reliability of DMPK prediction. The fluorescent probes may bridge the gap between conventional models and in vivo clinical studies in humans and provide a consistent basis for DMPK assay development.
... UGTs, important biochemical factors of cellular defense and detoxification, play an important role in the metabolism of many clinical drugs or their phase I metabolites [20]. Therefore, inhibition of UGT-catalyzed glucuronidation reactions is the key reason for testing clinical herb-drug interaction, because many xenobiotics have been demonstrated to have inhibitory effects against UGTscatalyzed reactions, such as efavirenz [21], corydaline [22], and glycyrrhetinic acid [23]. ...
Bavachalcone and corylin are two major bioactive compounds isolated from
Psoralea corylifolia
L., which has been widely used as traditional Chinese medicine for many years. As two antibiotic or anticancer drugs, bavachalcone and corylin are used in combination with other drugs; thus it is necessary to evaluate potential pharmacokinetic herb-drug interactions (HDI) of the two bioactive compounds. The aim of the present study was to compare the effects of liver UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT1A7, UGT1A8, UGT 1A10, and UGT2B4 inhibited by bavachalcone and corylin. 4-Methylumbelliferone (4-MU) was used as a nonspecific “probe” substrate. Bavachalcone had stronger inhibition on UGT1A1 and UGT1A7 than corylin which did not inhibit UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A10, and UGT2B4. Data fitting using Dixon and Lineweaver-Burk plots demonstrated the noncompetitive inhibition of bavachalcone against UGT1A1 and UGT1A7-mediated 4-MU glucuronidation reaction. The values of inhibition kinetic parameters (Ki) were 5.41
μ
M and 4.51
μ
M for UGT1A1 and UGT1A7, respectively. The results of present study suggested that there was a possibility of UGT1A1 and UGT1A7 inhibition-based herb-drug interaction associated with bavachalcone and provided the basis for further in vivo studies to investigate the HDI potential between bavachalcone and UGT substrates.
... Honokiol was shown to be a potent competitive inhibitor of CYP2C19, with a K i value of 0.57 μM, indicating that honokiol should be used carefully with CYP2C19 substrates such as diazepam, phenytoin, amitriptyline, imipramine, lansoprazole, and omeprazole in order to avoid drug interactions [46]. In addition, some natural compounds, including anthocyanidin [47], beauvericin [48], corydaline [49], eupatilin [50], and ursolic acid [51] have demonstrated strong inhibition of CYP2C19. ...
... All incubations were performed in triplicate and the mean values were used. Glucuronides produced from UGT isoform-specific substrates were determined by LC-MS/MS [49]. ...
Honokiol is a bioactive component isolated from the medicinal herbs Magnolia officinalis and Magnolia grandiflora that has antioxidative, anti-inflammatory, antithrombotic, and antitumor activities. The inhibitory potentials of honokiol on eight major human cytochrome P450 (CYP) enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, and four UDP-glucuronosyltransferases (UGTs) 1A1, 1A4, 1A9, and 2B7 in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Honokiol strongly inhibited CYP1A2-mediated phenacetin O-deethylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4-hydroxylation, and UGT1A9-mediated propofol glucuronidation with Ki values of 1.2, 4.9, 0.54, 0.57, and 0.3 μM, respectively. Honokiol also moderately inhibited CYP2B6-mediated bupropion hydroxylation and CYP2D6-mediated bufuralol 1'-hydroxylation with Ki values of 17.5 and 12.0 μM, respectively. These in vitro results indicate that honokiol has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and UGT1A9.
... All incubations were performed in triplicate and the mean values were used. The glucuronides produced from UGT isoform-specific substrates were respectively determined by LC/MS/MS [21]. The system consisted of a tandem quadrupole mass spectrometer (TSQ Quantum Access, ThermoFisher Scientific, San Jose, CA, USA) coupled with a Nanospace SI-2 LC system (Shiseido, Tokyo, Japan). ...
Efavirenz is a non-nucleoside reverse transcriptase inhibitor used for the treatment of human immunodeficiency virus type 1 infections. Drug interactions of efavirenz have been reported due to in vitro inhibition of CYP2C9, CYP2C19, CYP3A4, and UDP-glucuronosyltransferase 2B7 (UGT2B7) and in vivo CYP3A4 induction. The inhibitory potentials of efavirenz on the enzyme activities of four major UDP-glucuronosyltransferases (UGTs), 1A1, 1A4, 1A6, and 1A9, in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Efavirenz potently inhibited UGT1A4-mediated trifluoperazine N-glucuronidation and UGT1A9-mediated propofol glucuronidation, with K(i) values of 2.0 and 9.4 μM, respectively. [I]/K(i) ratios of efavirenz for trifluoperazine N-glucuronidation and propofol glucuronidation were 6.5 and 1.37, respectively. Efavirenz also moderately inhibited UGT1A1-mediated 17β-estradiol 3-glucuronidation, with a K(i) value of 40.3 μM, but did not inhibit UGT1A6-mediated 1-naphthol glucuronidation. Those in vitro results suggest that efavirenz should be examined for potential pharmacokinetic drug interactions in vivo due to strong inhibition of UGT1A4 and UGT1A9.
... Quantification was performed by SRM of the [M + H]+ ion for trifluoperazine glucuronide and azidothymidine glucuronide or [M − H]− for etoposide glucuronide and propofol glucuronide and the related product ion for each metabolite. SRM transitions for the metabolites and internal standard are summarized in our previous paper [23]. Analytical data were processed using Xcalibur software (Thermo Fisher Scientific). ...
... The inhibitory potencies (IC50 values) of DA-9701, Corydalis tuber extract, or Pharbitidis semen extract were also determined with UGT assays in the presence and absence of DA-9701, Corydalis tuber extract, or Pharbitidis semen extract using pooled human liver microsomes. Etoposide glucuronidation, trifluoperazine glucuronidation, propofol glucuronidation, and azidothymidine glucuronidation activities were determined as probe activities for UGT1A1, UGT1A4, UGT1A9, and UGT2B7, respectively, using LC/MS/MS [23]. Incubation mixtures were prepared in a total volume of 100 μL as follows: pooled human liver microsomes (0.2 mg/mL for etoposide, trifluoperazine, and azidothymidine; 0.1 mg/mL for propofol), 25 μg/mL alamethicin, 10 mM MgCl2, 50 mM tris buffer (pH 7.4), each UGT-isoform specific probe substrate (200 μM etoposide for UGT1A1, 5 μM trifluoperazine for UGT1A4, 10 μM propofol for UGT1A9, or 100 μM azidothymidine for UGT2B7), and various concentrations of DA-9701, Corydalis tuber extract, or Pharbitidis semen extract (final concentrations of 1–200 μg/mL with acetonitrile concentration less than 0.5% v/v). ...
... DA-9701, Corydalis tuber extract, and Pharbitidis semen extract at 200 μg/mL showed negligible inhibition on CYP1A2-mediated phenacetin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4′-hydroxylation, and CYP3A-mediated midazolam 1′-hydroxylation. IC50 values of corydaline and palmatine, the marker compounds of DA-9701 for CYP2D6-catalyzed bufuralol 1′-hydroxylation activity were 23.8 [23] and 49.3 μg/mL (our unpublished data), respectively. ...
DA-9701 is a new botanical drug composed of the extracts of Corydalis tuber and Pharbitidis semen, and it is used as an oral therapy for the treatment of functional dyspepsia in Korea. The inhibitory potentials of DA-9701 and its component herbs, Corydalis tuber and Pharbitidis semen, on the activities of seven major human cytochrome P450 (CYP) enzymes and four UDP-glucuronosyltransferase (UGT) enzymes in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. DA-9701 and Corydalis tuber extract slightly inhibited UGT1A1-mediated etoposide glucuronidation, with 50% inhibitory concentration (IC(50)) values of 188 and 290 μg/mL, respectively. DA-9701 inhibited CYP2D6-catalyzed bufuralol 1'-hydroxylation with an inhibition constant (K(i)) value of 6.3 μg/mL in a noncompetitive manner. Corydalis tuber extract competitively inhibited CYP2D6-mediated bufuralol 1'-hydroxylation, with a K(i) value of 3.7 μg/mL, whereas Pharbitidis semen extract showed no inhibition. The volume in which the dose could be diluted to generate an IC(50) equivalent concentration (volume per dose index) value of DA-9701 for inhibition of CYP2D6 activity was 1.16 L/dose, indicating that DA-9701 may not be a potent CYP2D6 inhibitor. Further clinical studies are warranted to evaluate the in vivo extent of the observed in vitro interactions.
Allergic disorders pose a significant global health challenge, impacting millions. Plants, rich in bioactive compounds, have gained recognition for their potential to alleviate various allergic symptoms. The demand for effective antiallergic agents has spurred research into harnessing the therapeutic potential of plant-derived metabolites. Therefore, as the need for sustainable, nature-based therapeutic options grows, biotechnological strategies have become powerful tools for amplifying the production of antiallergic metabolites. This chapter delves into biotechnological approaches for producing antiallergic metabolites from plants. Specifically, the study investigates the use of in vitro systems, such as callus and cell suspension cultures, as well as elicitor interventions, to augment the production of secondary metabolites exhibiting antiallergic properties. The integration of genetic fidelity assessment and molecular techniques ensures the quality and consistency of the produced compounds. Researchers have employed in vitro systems to yield secondary metabolites targeting allergic responses by leveraging plants’ inherent capabilities and advanced techniques. The chapter sheds light on methodologies aimed at bolstering the production of compounds targeting allergic reactions, encompassing antiasthmatic, antihistaminic, and anti-itching agents. This chapter contributes to understanding innovative strategies for harnessing plant-derived compounds to combat allergies by offering insights into these biotechnological methodologies. Besides, our study aims to equip researchers, practitioners, and healthcare professionals with a roadmap to navigate the promising plant antiallergic metabolite production horizon.
Background
Jitai tablet, a traditional Chinese medicine, has a neuroprotective effect on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mice. As one of the main active ingredients in the Jitai tablet, corydaline (Cory) has analgesic and anti-allergic effects, but it has not been studied in PD. Here, we investigated the role and mechanism of Cory in PD.
Methods
The PD model was induced by MPTP. Cell viability was measured by 3-(4, 5)-dimethylthiahiazo (-z-y1)-3, 5-di-phenytetrazoliumromide assay. The Pole test and traction test were performed to detect the behaviors of mice. The expression of tyrosine hydroxylase (Th) was detected by immunohistochemistry and Western blot. Immunofluorescence staining, monodansylcadaverine staining, and Western blot were conducted to assess autophagy. A lactic dehydrogenase release assay was used to detect cytotoxicity. Network pharmacology was used to screen the targets.
Results
There existed cytotoxicity when the concentration of Cory reached 40 μg/mL. Cory (not exceeding 20 μg/mL) could alleviate MPTP-induced cell damage. In vivo experiments indicated that Cory could improve the motor coordination of mice with PD. Besides, Cory could increase LC3-II/LC3-I levels both in vivo and in vitro. In addition, the Th levels reduced in the striatum and middle brain tissues of Parkinson’s mice were recovered by Cory injection. We also found that Cory decreased the phosphorylation of glucogen synthase kinase-3 beta (GSK-3β) at Tyr216 and increased the phosphorylation of GSK-3β at Ser9 not only in primary neurons and SH-SY5Y cells but also in the striatum and middle brain tissues. Furthermore, Cory increased LC3-II/LC3-I levels and decreased p62 levels by regulating GSK-3β.
Conclusion
Cory enhanced autophagy, attenuated MPTP-induced cytotoxicity, and alleviated PD partly through the regulation of GSK-3β phosphorylation.
