Skip to content
2000
Volume 25, Issue 9
  • ISSN: 1389-2002
  • E-ISSN: 1875-5453

Abstract

Background

Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic enzyme that is overexpressed in many tumors and is associated with tumor development and acquired resistance. Few studies have reported that anthraquinone compounds have inhibitory activity against the CYP1B1 enzyme. (Leguminosae) is a well-known traditional Chinese medicine containing more than 70 compounds. The crude extracts and pure compounds of have been widely used in preclinical and clinical practice for their beneficial effects, such as neuroprotective, hepatoprotective, antimicrobial, antioxidant, and hypotensive effects. Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein are important active natural anthraquinones in Cassiae semen.

Objective

Aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin, and rhein have a wide range of pharmacological activities and have been found to have good anti-tumor and antioxidant effects. However, the underlying mechanisms of these pharmacological activities remain poorly understood. This study aimed to investigate the inhibitory effects of five natural anthraquinones on the activity of CYP1B1 and to analyze the structure-activity relationship of these compounds.

Materials and Methods

In this study, 7-ethoxyresorufin O-deethylation (EROD) was used as the fluorescent substrate of CYP1B1 to investigate the inhibition effect, and molecular docking was performed to further determine the structural-activity relationship of the compound molecules.

Results

We found that aloe-emodin and chrysophanol had strong inhibitory effects on CYP1B1 with IC values of 0.28 and 0.34μM, respectively, while obtusifolin and aurantio-obtusin had IC values of 0.77μM and 9.11μM, respectively. The structural activity analysis showed that the inhibition strength was related to the position of the hydroxyl group substitution and the number of methoxy group substitutions. Rhein containing one carboxyl group showed the weakest inhibition of 23.72μM. The inhibition kinetics showed that all five compounds belonged to the non-competitive inhibition model. The inhibition kinetics revealed that all five compounds exhibited the non-competitive inhibition model.

Conclusion

The present study provided a comprehensive analysis of the inhibitory effects of five natural anthraquinones, namely aloe-emodin, chrysophanol, obtusifolin, aurantio-obtusin and rhein, on CYP1B1 activity, and elucidated the structure-activity relationship. Molecular docking simulations further revealed the specific amino acid residues within the active site of CYP1B1, where these compounds exerted their actions. These findings offer novel insights into investigating the potential antitumor properties of natural anthraquinones.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdm/10.2174/0113892002329282250108163208
2025-01-20
2025-10-14

  • From This Site

    /content/journals/cdm/10.2174/0113892002329282250108163208
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. DongX. FuJ. YinX. YangC. ZhangX. WangW. DuX. WangQ. NiJ. Cassiae semen: A review of its phytochemistry and pharmacology.Mol. Med. Rep.20171632331234610.3892/mmr.2017.688028677746
     [Google Scholar]
  2. ChenY. ChenX. YangX. GaoP. YueC. WangL. WuT. JiangT. WuH. TangL. WangZ. Cassiae Semen: A comprehensive review of botany, traditional use, phytochemistry, pharmacology, toxicity, and quality control.J. Ethnopharmacol.202330611619910.1016/j.jep.2023.11619936702448
     [Google Scholar]
  3. PangX. LiN. YuH.S. KangL.P. YuH.Y. SongX.B. FanG.W. HanL.F. Two new naphthalene glycosides from the seeds of Cassia obtusifolia.J. Asian Nat. Prod. Res.2019211097097610.1080/10286020.2018.147881629947250
     [Google Scholar]
  4. PaudelP. SeongS.H. ShresthaS. JungH.A. ChoiJ.S. In vitro and in silico human monoamine oxidase inhibitory potential of anthraquinones, naphthopyrones, and naphthalenic lactones from cassia obtusifolia linn seeds.ACS Omega2019414161391615210.1021/acsomega.9b0232831592482
     [Google Scholar]
  5. ChoiJ. LeeH. ParkK.Y. HaJ.O. KangS. In vitro antimutagenic effects of anthraquinone aglycones and naphthopyrone glycosides from Cassia tora.Planta Med.1997631111410.1055/s‑2006‑9575939063089
     [Google Scholar]
  6. YenG.C. ChenH.W. DuhP.D. Extraction and identification of an antioxidative component from Jue Ming Zi (Cassia tora L.).J. Agric. Food Chem.199846382082410.1021/jf970690z
     [Google Scholar]
  7. TianW. WangC. LiD. HouH. Novel anthraquinone compounds as anticancer agents and their potential mechanism.Future Med. Chem.202012762764410.4155/fmc‑2019‑032232175770
     [Google Scholar]
  8. JiangD. DingS. MaoZ. YouL. RuanY. Integrated analysis of potential pathways by which aloe-emodin induces the apoptosis of colon cancer cells.Cancer Cell Int.202121123810.1186/s12935‑021‑01942‑833902610
     [Google Scholar]
  9. HsuY.L. TsaiE.M. HouM.F. WangT.N. HungJ.Y. KuoP.L. Obtusifolin suppresses phthalate esters-induced breast cancer bone metastasis by targeting parathyroid hormone-related protein.J. Agric. Food Chem.20146249119331194010.1021/jf504290525415928
     [Google Scholar]
  10. ZhangH. MaL. KimE. YiJ. HuangH. KimH. RazaM.A. ParkS. JangS. KimK. KimS.H. LeeY. KimE. RyooZ.Y. KimM.O. Rhein induces oral cancer cell apoptosis and ros via suppresse akt/mtor signaling pathway in vitro and in vivo.Int. J. Mol. Sci.20232410850710.3390/ijms2410850737239855
     [Google Scholar]
  11. HevirN. ŠinkovecJ. RižnerT.L. Disturbed expression of phase I and phase II estrogen-metabolizing enzymes in endometrial cancer: Lower levels of CYP1B1 and increased expression of S-COMT.Mol. Cell. Endocrinol.2011331115816710.1016/j.mce.2010.09.01120887769
     [Google Scholar]
  12. McKayJ.A. MelvinW.T. Ah-SeeA.K. EwenS.W.B. GreenleeW.F. MarcusC.B. BurkeM.D. MurrayG.I. Expression of cytochrome P450 CYP1B1 in breast cancer.FEBS Lett.1995374227027210.1016/0014‑5793(95)01126‑Y7589551
     [Google Scholar]
  13. MurrayG.I. TaylorM.C. McFadyenM.C. McKayJ.A. GreenleeW.F. BurkeM.D. MelvinW.T. Tumor-specific expression of cytochrome P450 CYP1B1.Cancer Res.19975714302630319230218
     [Google Scholar]
  14. AndroutsopoulosV.P. SpyrouI. PloumidisA. PapalamprosA.E. KyriakakisM. DelakasD. SpandidosD.A. TsatsakisA.M. Expression profile of CYP1A1 and CYP1B1 enzymes in colon and bladder tumors.PLoS One2013812e8248710.1371/journal.pone.008248724358191
     [Google Scholar]
  15. ShimadaT. HayesC.L. YamazakiH. AminS. HechtS.S. GuengerichF.P. SutterT.R. Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1.Cancer Res.19965613297929848674051
     [Google Scholar]
  16. BoltonJ.L. ThatcherG.R.J. Potential mechanisms of estrogen quinone carcinogenesis.Chem. Res. Toxicol.20082119310110.1021/tx700191p18052105
     [Google Scholar]
  17. SissungT.M. PriceD.K. SparreboomA. FiggW.D. Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention.Mol. Cancer Res.20064313515010.1158/1541‑7786.MCR‑05‑010116547151
     [Google Scholar]
  18. NishidaC.R. EverettS. Ortiz de MontellanoP.R. Specificity determinants of CYP1B1 estradiol hydroxylation.Mol. Pharmacol.201384345145810.1124/mol.113.08770023821647
     [Google Scholar]
  19. MartinezV.G. O’ConnorR. LiangY. ClynesM. CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance.Br. J. Cancer200898356457010.1038/sj.bjc.660419518212750
     [Google Scholar]
  20. LinH. HuB. HeX. MaoJ. WangY. WangJ. ZhangT. ZhengJ. PengY. ZhangF. Overcoming Taxol-resistance in A549 cells: A comprehensive strategy of targeting P-gp transporter, AKT/ERK pathways, and cytochrome P450 enzyme CYP1B1 by 4-hydroxyemodin.Biochem. Pharmacol.202017111373310.1016/j.bcp.2019.11373331783010
     [Google Scholar]
  21. ZhouB. XiaoX. XuL. ZhuL. TanL. TangH. ZhangY. XieQ. YaoS. A dynamic study on reversal of multidrug resistance by ginsenoside Rh2 in adriamycin-resistant human breast cancer MCF-7 cells.Talanta20128834535110.1016/j.talanta.2011.10.05122265509
     [Google Scholar]
  22. McFadyenM.C.E. McLeodH.L. JacksonF.C. MelvinW.T. DoehmerJ. MurrayG.I. Cytochrome P450 CYP1B1 protein expression.Biochem. Pharmacol.200162220721210.1016/S0006‑2952(01)00643‑811389879
     [Google Scholar]
  23. ChenC. MinY. LiX. ChenD. ShenJ. ZhangD. SunH. BianQ. YuanH. WangS.L. Mutagenicity risk prediction of PAH and derivative mixtures by in silico simulations oriented from CYP compound I-mediated metabolic activation.Sci. Total Environ.202178714759610.1016/j.scitotenv.2021.14759633991922
     [Google Scholar]
  24. ShiizakiK. KawanishiM. YagiT. Modulation of benzo[a]pyrene–DNA adduct formation by CYP1 inducer and inhibitor.Genes Environ.20173911410.1186/s41021‑017‑0076‑x28405246
     [Google Scholar]
  25. UnoS. DaltonT.P. DerkenneS. CurranC.P. MillerM.L. ShertzerH.G. NebertD.W. Oral exposure to benzo[a]pyrene in the mouse: detoxication by inducible cytochrome P450 is more important than metabolic activation.Mol. Pharmacol.20046551225123710.1124/mol.65.5.122515102951
     [Google Scholar]
  26. TalaskaG. GinsburgD. LaDowK. PugaA. DaltonT. WarshawskyD. Impact of Cyp1a2 or Ahr gene knockout in mice: Implications for biomonitoring studies.Toxicol. Lett.20061622-324624910.1016/j.toxlet.2005.09.02016256281
     [Google Scholar]
  27. MaayahZ.H. AlthurwiH.N. AbdelhamidG. LesykG. JuraszP. El-KadiA.O.S. CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid-chain HETEs-dependent mechanism.Pharmacol. Res.2016105284310.1016/j.phrs.2015.12.01626772815
     [Google Scholar]
  28. CarreraA.N. GrantM.K.O. ZordokyB.N. CYP1B1 as a therapeutic target in cardio-oncology.Clin. Sci. (Lond.)2020134212897292710.1042/CS2020031033185690
     [Google Scholar]
  29. HanX. ChengY. JiangZ. AluA. MaX. Honokiol exhibits anti-tumor effects in breast cancer by modulating the miR-148a-5p-CYP1B1 axis.Am. J. Chin. Med.20245261843186110.1142/S0192415X2450072139347954
     [Google Scholar]
  30. YangM. YangF. HuangX. CaiJ. ZhangY. JiaJ. QiuD. Design of novel 2-phenylquinazolin-4-amines as selective CYP1B1 inhibitors for overcoming paclitaxel resistance in A549 cells.J. Med. Chem.20246775883590110.1021/acs.jmedchem.4c0016438509663
     [Google Scholar]
  31. LiF. ZhuW. GonzalezF.J. Potential role of CYP1B1 in the development and treatment of metabolic diseases.Pharmacol. Ther.2017178183010.1016/j.pharmthera.2017.03.00728322972
     [Google Scholar]
  32. SinghJ. HussainY. LuqmanS. MeenaA. Purpurin: A natural anthraquinone with multifaceted pharmacological activities.Phytother. Res.2020355241824283325428210.1002/ptr.6965
     [Google Scholar]
  33. TsuchiyaY. NakajimaM. YokoiT. Cytochrome P450-mediated metabolism of estrogens and its regulation in human.Cancer Lett.2005227211512410.1016/j.canlet.2004.10.00716112414
     [Google Scholar]
  34. BulusH. OguztuzunS. Güler SimsekG. KilicM. AdaA.O. GölS. KocdoganA.K. KaygınP. BozerB. IscanM. Expression of CYP and GST in human normal and colon tumor tissues.Biotech. Histochem.20199411910.1080/10520295.2018.149322030092668
     [Google Scholar]
  35. SasakiM. KaneuchiM. FujimotoS. TanakaY. DahiyaR. CYP1B1 gene in endometrial cancer.Mol. Cell. Endocrinol.20032021-217117610.1016/S0303‑7207(03)00079‑012770747
     [Google Scholar]
  36. FabrisM. Luiza SilvaM. de Santiago-SilvaK.M. de Lima Ferreira BispoM. Goes CamargoP. CYP1B1: A promising target in cancer drug discovery.Anticancer. Agents Med. Chem.202323998198810.2174/187152062366623011910391436655529
     [Google Scholar]
  37. MurrayG.I. The role of cytochrome P450 in tumour development and progression and its potential in therapy.J. Pathol.2000192441942610.1002/1096‑9896(2000)9999:9999<::AID‑PATH750>3.0.CO;2‑011113857
     [Google Scholar]
  38. RochatB. MorsmanJ.M. MurrayG.I. FiggW.D. McLeodH.L. Human CYP1B1 and anticancer agent metabolism: Mechanism for tumor-specific drug inactivation?.J. Pharmacol. Exp. Ther.2001296253754111160641
     [Google Scholar]
  39. PiscagliaF. KnittelT. KoboldD. Barnikol-WatanabeS. Di RoccoP. RamadoriG. Cellular localization of hepatic cytochrome 1B1 expression and its regulation by aromatic hydrocarbons and inflammatory cytokines.Biochem. Pharmacol.199958115716510.1016/S0006‑2952(99)00066‑010403529
     [Google Scholar]
  40. BaurJ.A. SinclairD.A. Therapeutic potential of resveratrol: The in vivo evidence.Nat. Rev. Drug Discov.20065649350610.1038/nrd206016732220
     [Google Scholar]
  41. LamyS. BédardV. LabbéD. SarteletH. BarthomeufC. GingrasD. BéliveauR. The dietary flavones apigenin and luteolin impair smooth muscle cell migration and VEGF expression through inhibition of PDGFR-beta phosphorylation.Cancer Prev. Res. (Phila.)20081645245910.1158/1940‑6207.CAPR‑08‑007219138992
     [Google Scholar]
  42. WooK.J. JeongY.J. InoueH. ParkJ.W. KwonT.K. Chrysin suppresses lipopolysaccharide-induced cyclooxygenase-2 expression through the inhibition of nuclear factor for IL-6 (NF-IL6) DNA-binding activity.FEBS Lett.2005579370571110.1016/j.febslet.2004.12.04815670832
     [Google Scholar]
  43. YangJ. WangS. ZhangT. SunY. HanL. BanaheneP.O. WangQ. Predicting the potential toxicity of 26 components in Cassiae semen using in silico and in vitro approaches.Curr. Res. Toxicol.2021223724510.1016/j.crtox.2021.06.00134345866
     [Google Scholar]
  44. ChengG. PiZ. ZhuangX. ZhengZ. LiuS. LiuZ. SongF. The effects and mechanisms of aloe-emodin on reversing adriamycin-induced resistance of MCF-7/ ADR cells.Phytother. Res.20213573886389710.1002/ptr.709633792091
     [Google Scholar]
  45. LiY. JiangJ.G. Health functions and structure–activity relationships of natural anthraquinones from plants.Food Funct.20189126063608010.1039/C8FO01569D30484455
     [Google Scholar]
  46. DongJ. WangZ. CuiJ. MengQ. LiS. Synthesis and structure-activity relationship studies of α-naphthoflavone derivatives as CYP1B1 inhibitors.Eur. J. Med. Chem.202018711193810.1016/j.ejmech.2019.11193831830634
     [Google Scholar]
  47. ZhaoT. ChenX. YuH. DuJ. WangD. WangC. MengQ. SunH. LiuK. WuJ. Unraveling the structure-dependent inhibitory effects of ginsenoside series compounds on human cytochrome P450 1B1.Curr. Drug Metab.202223755356110.2174/138920022366622060110262935652395
     [Google Scholar]
  48. ChenX. ZhaoT. DuJ. GuanX. YuH. WangD. Comparative inhibitory effects of natural biflavones from ginkgo against human CYP1B1 in recombinant enzymes and MCF-7 Cells.Planta Med.20228943974073606411510.1055/a‑1936‑4807
     [Google Scholar]
/content/journals/cdm/10.2174/0113892002329282250108163208
Loading
Characterization of Five Natural Anthraquinone Compounds as Potent Inhibitors against CYP1B1: Implications for Cancer Treatment
Current Drug Metabolism 25, 677 (2024); https://doi.org/10.2174/0113892002329282250108163208
/content/journals/cdm/10.2174/0113892002329282250108163208
/content/journals/cdm/10.2174/0113892002329282250108163208
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): cancer; CYP1B1; enzyme inhibition; kinetics of inhibition; natural anthraquinones; structure-activity relationship

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test