Inhibitory Effects of Dimethyllirioresinol, Epimagnolin A, Eudesmin, Fargesin, and Magnolin on Cytochrome P450 Enzyme Activities in Human Liver Microsomes

Kim, Ju-Hyun; Kwon, Soon-Sang; Jeong, Hyun Cheol; Lee, Hye Suk

doi:10.3390/ijms18050952

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…Epimagnolin (Figure 1A), a natural lignan compound abundantly found in Magnolia flos, has a very similar chemical structure to those of magnolin 29 and aschantin. 30 Our previous studies demonstrated that magnolin and aschantin suppressed tumor promoter-induced carcinogenesis and cancer cell proliferation.…”

Section: Epimagnolin Suppresses Cell Proliferation By Inhibition Ofmentioning

confidence: 99%

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Yoo

Lee

Kang

et al. 2019

Molecular Carcinogenesis

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Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin‐Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)‐induced G1/S cell‐cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF‐induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal‐regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c‐Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP‐1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate‐bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage‐independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage‐independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR‐Akt‐p70S6K and mTOR‐Akt‐GSK3β‐AP‐1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2‐Akt‐p70S6k signaling pathway.

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Section: Epimagnolin Suppresses Cell Proliferation By Inhibition Ofmentioning

confidence: 99%

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Yoo

Lee

Kang

et al. 2019

Molecular Carcinogenesis

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“…Previously, fargesin from the Magnolia plants which are used in the treatment of headache, nasal congestion and sinusitis was shown to improve dyslipidemia and hyperglycemia in high fat-induced obese mice by phosphorylating and activating Akt, AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase in both 3T3-L1 adipocytes and white adipose tissue (Lee et al 2012 ). In addition, in vitro inhibitory activities of fargesin from Flos Magnoliae on eight different cytochrome P450 enzymes were determined suggesting that fargesin may modulate drug metabolism, but more in vivo studies are required to investigate drug interactions (Kim et al 2017 ). A recent study showed that fargesin inhibits atherosclerosis by promoting reverse cholesterol transport process and reduced inflammatory response via CEBPαS21/LXRα and TLR4/NF-κB pathways (Wang et al 2020 ) Similarly, alteration of CYP46A1 and HMG-CoA reductase on Lipopolysaccharide stimulation through TLR4/MyD88/NF-κB signalling pathway leading to neuroinflammation has been reported (Na et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants

et al. 2022

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Cytochrome P450 46A1 (CYP46A1) is a crucial enzyme in brain that converts cholesterol to 24 (S) hydroxy cholesterol thereby increasing its polarity to facilitate removal of excess cholesterol from the CNS. The inhibition of CYP46A1 with several synthetic molecules has been investigated extensively for treatment of Alzheimer’s disease, Huntington’s disease, glaucoma, and in hippocampal neurons from aged mice. However, phytochemicals have received far little attention in studies involving development of potential CYP46A1 inhibitors. Thus, in the present study phytoconstituents from Indian traditional medicinal plants; Bacopa monnieri , Piper longum, and Withania somnifera, were virtually screened for interaction with CYP46A1 using computational tools. Out of three plants, six molecules from P. longum and three molecules from W. somnifera were shortlisted to study interactions with CYP46A1 based on the physio-chemical parameters. Fargesin, piperolactam A and coumaperine from P. longum showed the higher binding affinity and the values were − 10.3, − 9.5, − 9.0 kcal/moles respectively, whereas, withaferin A from W. somnifera had a binding affinity of − 12.9 kcal/mol. These were selected as potential modulators as they exhibited suitable interactions with active site residues; Tyr109, Leu112, Trp368, Gly369, and Ala474. The selected molecules were further subjected to molecular dynamics simulation. Further, the pharmacological properties of molecules were also predicted using ADMET calculator and the data revealed that all the selected compounds had good absorption as well as solubility characteristics. In addition, sesamin, fargesin, piperolactam A, and coumaperine had minimal or no toxic effects. Thus, the study successfully identified compounds from Indian medicinal plants that may serve as potential inhibitors of CYP46A1 or base structures to design novel CYP46A1 inhibitors, which may be effective in treating neurological conditions involving perturbed cholesterol homeostasis. Supplementary Information The online version contains supplementary material available at 10.1007/s42485-022-00098-x.

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Section: Introductionmentioning

confidence: 99%

“…The inhibitory effects of yangambin, epimagnolin A, eudesmin, fargesin, and magnolin on CYP activities in human liver microsomes were previously investigated [ 30 ]. Fargesin inhibited competitively CYP2C9-catalyzed diclofenac 4′-hydroxylation ( K i , 16.3 μM) [ 30 ]. It also exhibited the time-dependent inhibition of CYP2C8 ( K i : 10.7 µM and k inact : 0.082 min −1 ), CYP2C19 ( K i : 3.7 µM and k inact : 0.102 min −1 ), and CYP3A4 ( K i : 23.0 µM and k inact : 0.050 min −1 ) in human liver microsomes.…”

Section: Introductionmentioning

confidence: 99%

“…However, fargesin negligibly inhibited the catalytic activities of CYP1A2, CYP2A6, CYP2B6, and CYP2D6. In addition, eudesmin, epimagnolin A, magnolin, and yangambin slightly inhibited eight major CYP activities in human liver microsomes, indicating that they may not cause CYP-mediated drug interactions [ 30 ]. However, no reports exist on in vitro and in vivo inhibitory effects of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on human UGT enzymes.…”

Section: Introductionmentioning

confidence: 99%

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Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes

Park

Cho

et al. 2021

Pharmaceutics

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Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated using liquid chromatography–tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 μM in pooled human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, 26.0, and 17.1 μM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 37.6, and 66.8 μM, respectively in pooled human liver microsomes. These in vitro results suggest the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug–drug interactions with UGT1A1 and UGT1A3 substrates in vivo.

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Inhibitory Effects of Dimethyllirioresinol, Epimagnolin A, Eudesmin, Fargesin, and Magnolin on Cytochrome P450 Enzyme Activities in Human Liver Microsomes

Cited by 11 publications

References 43 publications

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

Identification of potential inhibitors of brain-specific CYP46A1 from phytoconstituents in Indian traditional medicinal plants

Tetrahydrofurofuranoid Lignans, Eudesmin, Fargesin, Epimagnolin A, Magnolin, and Yangambin Inhibit UDP-Glucuronosyltransferase 1A1 and 1A3 Activities in Human Liver Microsomes

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