Skip to main content
SpringerLink
Log in

Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes

  • Original Article
  • Published:
Toxicological Research Aims and scope Submit manuscript

Abstract

Fargesin, a bioactive lignan derived from Flos Magnoliae, possesses anti-inflammatory, anti-oxidative, anti-melanogenic, and anti-apoptotic effects. This study compared the metabolic profiles of fargesin in human, dog, monkey, mouse, and rat hepatocytes using liquid chromatography-high resolution mass spectrometry. In addition, we investigated the human cytochrome P450 (CYP), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for fargesin metabolism. The hepatic extraction ratio of fargesin among the five species ranged from 0.59 to 0.78, suggesting that it undergoes a moderate-to-extensive degree of hepatic metabolism. During metabolism, fargesin generates three phase 1 metabolites, including fargesin catechol (M1) and O-desmethylfargesin (M2 and M3), and 11 phase 2 metabolites, including O-methyl-M1 (M4 and M5) via catechol O-methyltransferase (COMT), glucuronides of M1, M2, M4, and M5, and sulfates of M1–M5. The production of M1 from fargesin via O-demethylenation is catalyzed by CYP2C9, CYP3A4, CYP2C19, and CYP2C8 enzymes, whereas the formation of M2 and M3 (O-desmethylfargesin) is catalyzed by CYP2C9, CYP2B6, CYP2C19, CYP3A4, CYP1A2, and CYP2D6 enzymes. M4 is metabolized to M4 glucuronide by UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17 enzymes, whereas M4 sulfate is generated by multiple SULT enzymes. Fargesin is extensively metabolized in human hepatocytes by CYP, COMT, UGT, and SULT enzymes. These findings help to elucidate the pharmacokinetics and drug interactions of fargesin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

Data are available upon request.

References

  1. Shen Y, Li CG, Zhou SF, Pang EC, Story DF, Xue CC (2008) Chemistry and bioactivity of Flos Magnoliae, a Chinese herb for rhinitis and sinusitis. Curr Med Chem 15:1616–1627. https://doi.org/10.2174/092986708784911515

    Article  CAS  PubMed  Google Scholar 

  2. Hong PTL, Kim HJ, Kim WK, Nam JH (2021) Flos magnoliae constituent fargesin has an anti-allergic effect via ORAI1 channel inhibition. Korean J Physiol Pharmacol 25:251–258. https://doi.org/10.4196/kjpp.2021.25.3.251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baek JA, Lee YD, Lee CB, Go HK, Kim JP, Seo JJ, Rhee YK, Kim AM, Na DJ (2009) Extracts of Magnoliae flos inhibit inducible nitric oxide synthase via ERK in human respiratory epithelial cells. Nitric Oxide 20:122–128. https://doi.org/10.1016/j.niox.2008.10.003

    Article  CAS  PubMed  Google Scholar 

  4. Kim JS, Kim JY, Lee HJ, Lim HJ, Lee DY, Kim DH, Ryu JH (2010) Suppression of inducible nitric oxide synthase expression by furfuran lignans from flower buds of Magnolia fargesii in BV-2 microglial cells. Phytother Res 24:748–753. https://doi.org/10.1002/ptr.3028

    Article  CAS  PubMed  Google Scholar 

  5. Pham TH, Kim MS, Le MQ, Song YS, Bak Y, Ryu HW, Oh SR, Yoon DY (2017) Fargesin exerts anti-inflammatory effects in THP-1 monocytes by suppressing PKC-dependent AP-1 and NF-ĸB signaling. Phytomedicine 24:96–103. https://doi.org/10.1016/j.phymed.2016.11.014

    Article  CAS  PubMed  Google Scholar 

  6. Yue B, Ren YJ, Zhang JJ, Luo XP, Yu ZL, Ren GY, Sun AN, Deng C, Wang ZT, Dou W (2018) Anti-inflammatory effects of fargesin on chemically induced inflammatory bowel disease in mice. Molecules 23:1380. https://doi.org/10.3390/molecules23061380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lu J, Zhang H, Pan J, Hu Z, Liu L, Liu Y, Yu X, Bai X, Cai D, Zhang H (2021) Fargesin ameliorates osteoarthritis via macrophage reprogramming by downregulating MAPK and NF-κB pathways. Arthritis Res Ther 23:142. https://doi.org/10.1186/s13075-021-02512-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jun AY, Kim HJ, Park KK, Son KH, Lee DH, Woo MH, Chung WY (2014) Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts. Invest New Drugs 32:1–13. https://doi.org/10.1007/s10637-013-9969-0

    Article  CAS  PubMed  Google Scholar 

  9. Wang G, Gao J, He LH, Yu XH, Zhao ZW, Zou J, Wen FJ, Zhou L, Wan XJ, Tang CK (2020) Fargesin alleviates atherosclerosis by promoting reverse cholesterol transport and reducing inflammatory response. Biochim Biophys Acta Mol Cell Biol Lipids 1865:158633. https://doi.org/10.1016/j.bbalip.2020.158633

    Article  CAS  PubMed  Google Scholar 

  10. Wang X, Cheng Y, Xue H, Yue Y, Zhang W, Li X (2015) Fargesin as a potential β1 adrenergic receptor antagonist protects the hearts against ischemia/reperfusion injury in rats via attenuating oxidative stress and apoptosis. Fitoterapia 105:16–25. https://doi.org/10.1016/j.fitote.2015.05.016

    Article  CAS  PubMed  Google Scholar 

  11. Sha S, Xu D, Wang Y, Zhao W, Li X (2016) Antihypertensive effects of fargesin in vitro and in vivo via attenuating oxidative stress and promoting nitric oxide release. Can J Physiol Pharmacol 94:900–906. https://doi.org/10.1139/cjpp-2015-0615

    Article  CAS  PubMed  Google Scholar 

  12. Lee YS, Cha BY, Choi SS, Harada Y, Choi BK, Yonezawa T, Teruya T, Nagai K, Woo JT (2012) Fargesin improves lipid and glucose metabolism in 3T3-L1 adipocytes and high-fat diet-induced obese mice. BioFactors 38:300–308. https://doi.org/10.1002/biof.1022

    Article  CAS  PubMed  Google Scholar 

  13. Choi SS, Cha BY, Choi BK, Lee YS, Yonezawa T, Teruya T, Nagai K, Woo JT (2013) Fargesin, a component of Flos Magnoliae, stimulates glucose uptake in L6 myotubes. J Nat Med 67:320–326. https://doi.org/10.1007/s11418-012-0685-4

    Article  CAS  PubMed  Google Scholar 

  14. Lee GE, Lee CJ, An HJ, Kang HC, Lee HS, Lee JY, Oh SR, Cho SJ, Kim DJ, Cho YY (2021) Fargesin inhibits EGF-induced cell transformation and colon cancer cell growth by suppression of CDK2/Cyclin E signaling pathway. Int J Mol Sci 22:2073. https://doi.org/10.3390/ijms22042073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu T, Chai B, Shi Y, Dang Y, Ye X (2019) Fargesin inhibits melanin synthesis in murine malignant and immortalized melanocytes by regulating PKA/CREB and P38/MAPK signaling pathways. J Dermatol Sci 94:213–219. https://doi.org/10.1016/j.jdermsci.2019.03.004

    Article  CAS  PubMed  Google Scholar 

  16. Foti RS, Dalvie DK (2016) Cytochrome P450 and non-cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics. Drug Metab Dispos 44:1229–1245. https://doi.org/10.1124/dmd.116.071753

    Article  CAS  PubMed  Google Scholar 

  17. Hwang DK, Kim JH, Shin Y, Choi WG, Kim S, Cho YY, Lee JY, Kang HC, Lee HS (2019) Identification of catalposide metabolites in human liver and intestinal preparations and characterization of the relevant sulfotransferase, UDP-glucuronosyltransferase, and carboxylesterase enzymes. Pharmaceutics 11:355. https://doi.org/10.3390/pharmaceutics11070355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee MS, Lim CH, Bang YY, Lee HS (2022) Quantification of fargesin in mouse plasma using liquid chromatography-high resolution mass spectrometry: application to pharmacokinetics of fargesin in mice. Mass Spectro Lett 13:20–25. https://doi.org/10.5478/MSL.2022.13.1.20

    Article  CAS  Google Scholar 

  19. Zhang Z, Liu X, Cao W, Xiao X, Qu J, Zhao M, Li X (2016) Pharmacokinetics and tissue distribution of fargesin after oral administration in rats by high performance liquid chromatography. Curr Pharm Anal 12:379. https://doi.org/10.2174/1573412912666151211191600

    Article  CAS  Google Scholar 

  20. Kim JH, Kwon SS, Jeong H, Lee HS (2017) Inhibitory effects of dimethyllirioresinol, epimagnolin A, eudesmin, fargesin, and magnolin on cytochrome P450 enzyme activities in human liver microsomes. Int J Mol Sci 18:952. https://doi.org/10.3390/ijms18050952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Park R, Park EJ, Cho YY, Lee JY, Kang HC, Song IS, Lee HS (2021) Tetrahydrofurofuranoid lignans, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibit UDP-glucuronosyltransferase 1A1 and 1A3 activities in human liver microsomes. Pharmaceutics 13:187. https://doi.org/10.3390/pharmaceutics13020187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim JH, Kim DK, Choi WG, Ji HY, Choi JS, Song IS, Lee S, Lee HS (2020) In vitro metabolism of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, in human and animal hepatocytes. Pharmaceutics 12:865. https://doi.org/10.3390/pharmaceutics12090865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093–1095. https://doi.org/10.1023/a:1018943613122

    Article  CAS  PubMed  Google Scholar 

  24. Kong TY, Kim JH, Choi WG, Lee JY, Kim HS, Kim JY, In MK, Lee HS (2017) Metabolic characterization of (1-(5-fluoropentyl)-1H-indol-3-yl)(4-methyl-1-naphthalenyl)-methanone (MAM-2201) using human liver microsomes and cDNA-overexpressed cytochrome P450 enzymes. Anal Bioanal Chem 409:1667–1680. https://doi.org/10.1007/s00216-016-0113-9

    Article  CAS  PubMed  Google Scholar 

  25. Lee HS, Jeong TC, Kim JH (1998) In vitro and in vivo metabolism of myristicin in the rat. J Chromatogr B Biomed Sci Appl 705:367–372. https://doi.org/10.1016/s0378-4347(97)00531-8

    Article  CAS  Google Scholar 

  26. Yun CH, Lee HS, Lee HY, Yim SK, Kim KH, Kim E, Yea SS, Guengerich FP (2003) Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin. Toxicol Lett 137:143–150. https://doi.org/10.1016/s0378-4274(02)00397-1

    Article  CAS  PubMed  Google Scholar 

  27. Yang AH, He X, Chen JX, He LN, Jin CH, Wang LL, Zhang FL, An LJ (2015) Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2. Chem Biol Interact 237:133–140. https://doi.org/10.1016/j.cbi.2015.06.018

    Article  CAS  PubMed  Google Scholar 

  28. Zhang X, Qiao GX, Zhao GF, Zhao SF (2021) Characterization of the metabolites of irisflorentin by using ultra-high performance liquid chromatography combined with quadrupole/orbitrap tandem mass spectrometry. J Pharm Biomed Anal 203:114222. https://doi.org/10.1016/j.jpba.2021.114222

    Article  CAS  PubMed  Google Scholar 

  29. Yasuda K, Ikushiro S, Kamakura M, Ohta M, Sakaki T (2010) Metabolism of sesamin by cytochrome P450 in human liver microsomes. Drug Metab Dispos 38:2117–2123. https://doi.org/10.1124/dmd.110.035659

    Article  CAS  PubMed  Google Scholar 

  30. Yasuda K, Ikushiro S, Kamakura M, Munetsuna E, Ohta M, Sakaki T (2011) Sequential metabolism of sesamin by cytochrome P450 and UDP-glucuronosyltransferase in human liver. Drug Metab Dispos 39:1538–1545. https://doi.org/10.1124/dmd.111.039875

    Article  CAS  PubMed  Google Scholar 

  31. Yasuda K, Sakaki T (2012) How is sesamin metabolised in the human liver to show its biological effects? Expert Opin Drug Metab Toxicol 8:93–102. https://doi.org/10.1517/17425255.2012.637917

    Article  CAS  PubMed  Google Scholar 

  32. Li Y, Li M, Wang Z, Wen M, Tang J (2020) Identification of the metabolites of piperine via hepatocyte incubation and liquid chromatography combined with diode-array detection and high-resolution mass spectrometry. Rapid Commun Mass Spectrom 34:e8947. https://doi.org/10.1002/rcm.8947

    Article  CAS  PubMed  Google Scholar 

  33. Cheng C, Zhao S, Gu YL, Pang J, Zhao Y (2022) Characterization and identification of the metabolites of dihydromethysticin by ultra-high-performance liquid chromatography orbitrap high-resolution mass spectrometry. J Sep Sci 45:2914–2923. https://doi.org/10.1002/jssc.202200250

    Article  CAS  PubMed  Google Scholar 

  34. Chen X, Li Y (2021) Identification of the stable and reactive metabolites of tetrahydropiperine using ultrahigh-performance liquid chromatography combined with diode-array detection and high-resolution mass spectrometry. Rapid Commun Mass Spectrom 35:e8975. https://doi.org/10.1002/rcm.8975

    Article  CAS  PubMed  Google Scholar 

  35. Xie Q, Chen Y, Liu F, Zhong Z, Zhao K, Ling Z, Wang F, Tang X, Wang Z, Liu L, Liu X (2016) Interspecies differences in metabolism of deoxypodophyllotoxin in hepatic microsomes from human, monkey, rat, mouse and dog. Drug Metab Pharmacokinet 31:314–322. https://doi.org/10.1016/j.dmpk.2016.05.002

    Article  CAS  PubMed  Google Scholar 

  36. Sun D, Gao X, Wang Q, Krausz KW, Fang Z, Zhang Y, Xie C, Gonzalez FJ (2021) Metabolic map of the antiviral drug podophyllotoxin provides insights into hepatotoxicity. Xenobiotica 51:1047–1059. https://doi.org/10.1080/00498254.2021.1961920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Simonneaux G, Le Maux P (2006) Carbene complexes of heme proteins and iron porphyrin models. Top Organomet Chem 17:83–122. https://doi.org/10.1007/3418_006

    Article  CAS  Google Scholar 

  38. Kim DK, Liu K-H, Jeong JH, Ji HY, Oh SR, Lee H-K, Lee HS (2011) In vitro metabolism of magnolin and characterization of cytochrome P450 enzymes responsible for its metabolism in human liver microsomes. Xenobiotica 41:358–371. https://doi.org/10.3109/00498254.2010.549968

    Article  CAS  PubMed  Google Scholar 

  39. Xia Y, Pang H, Dou T, Wang P, Ge G (2018) Interspecies comparison in the COMT-mediated methylation of 3-BTD. RSC Adv 8:16278–16284. https://doi.org/10.1039/c8ra01938j

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jalkanen A, Lassheikki V, Torsti T, Gharib E, Lehtonen M, Juvonen RO (2021) Tissue and interspecies comparison of catechol-O-methyltransferase mediated catalysis of 6-O-methylation of esculetin to scopoletin and its inhibition by entacapone and tolcapone. Xenobiotica 51:268–278. https://doi.org/10.1080/00498254.2020.1853850

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT) (NRF-2023R1A2C2007632) and the Research Fund, 2021 of The Catholic University of Korea.

Author information

Author notes

  1. Min Seo Lee and Eun Jeong Park have contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy and BK21 Four-sponsored Advanced Program for SmartPharma Leaders, The Catholic University of Korea, Bucheon, 14662, Republic of Korea

    Min Seo Lee, Eun Jeong Park, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang & Hye Suk Lee

Authors
  1. Min Seo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun Jeong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Yeon Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joo Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han Chang Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hye Suk Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hye Suk Lee.

Ethics declarations

Conflict of interests

The authors have no conflicts of interest to declare.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, M.S., Park, E.J., Cho, YY. et al. Comparative metabolism of fargesin in human, dog, monkey, mouse, and rat hepatocytes. Toxicol Res. 40, 125–137 (2024). https://doi.org/10.1007/s43188-023-00211-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43188-023-00211-2

Keywords

Search

Navigation