Skip to main content
SpringerLink
Log in

Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species

  • Original Research Article
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background

Baicalein is the major bioactive flavonoid in some herb medicines and dietary plants; however, the detailed metabolism pathway of its major metabolite oroxylin A-7-O-β-d-glucuronide in human was not clear. It was important to illustrate the major metabolic enzymes that participate in its elimination for the clinic use of baicalein.

Objectives

We first revealed a two-step metabolism profile for baicalein and illustrated the combination of catechol-O-methyltransferase (COMT) and uridine diphosphate-glucuronosyltransferases (UGTs) in drug metabolism, further evaluated its bioactivity variation during drug metabolism.

Methods

The metabolism profiles were systematically characterized in different human biology preparations; after then, the anti-inflammatory activities of metabolites were evaluated in LPS-induced RAW264.7 cell.

Results

The first-step metabolite of baicalein was isolated and identified as oroxylin A; soluble-bound COMT (S-COMT) was the major enzyme responsible for its biotransformation. Specially, position 108 mutation of S-COMT significantly decreases the elimination. Meantime, oroxylin A was rapidly metabolized by UGTs, UGT1A1, -1A3, -1A6, -1A7, -1A8, -1A9, and -1A10 which were involved in the glucuronidation. Considerable species differences were observed with 1060-fold K m (3.05 ± 1.86–3234 ± 475 μM) and 330-fold CLint (5.93–1973 μL/min/mg) variations for baicalein metabolism. Finally, the middle metabolite oroxylin A exhibited a potent anti-inflammatory activity with the IC50 value of 28 μM.

Conclusion

The detailed kinetic parameters indicated that COMT provide convenience for the next glucuronidation; monkey would be a preferred animal model for the preclinical investigation of baicalein. Importantly, oroxylin A should be reconsidered in evaluating baicalein efficacy against inflammatory diseases.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Xing J, Chen X, Sun Y, Luan Y, Zhong D. Interaction of baicalin and baicalein with antibiotics in the gastrointestinal tract. J Pharm Pharmacol. 2005;57(6):743–50. doi:10.1211/0022357056244.

    Article  CAS  PubMed  Google Scholar 

  2. Rutherford K, Le Trong I, Stenkamp RE, Parson WW. Crystal structures of human 108V and 108M catechol O-methyltransferase. J Mol Biol. 2008;380(1):120–30. doi:10.1016/j.jmb.2008.04.040.

    Article  CAS  PubMed  Google Scholar 

  3. Lu QY, Zhang L, Eibl G, Go VL. Overestimation of flavonoid aglycones as a result of the ex vivo deconjugation of glucuronides by the tissue beta-glucuronidase. J Pharm Biomed Anal. 2014;88:364–9. doi:10.1016/j.jpba.2013.09.013.

    Article  CAS  PubMed  Google Scholar 

  4. Yu C, Zeng J, Yan Z, Ma Z, Liu S, Huang Z. Baicalein antagonizes acute megakaryoblastic leukemia in vitro and in vivo by inducing cell cycle arrest. Cell Biosci. 2016;6:20. doi:10.1186/s13578-016-0084-8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wang CZ, Zhang CF, Chen L, Anderson S, Lu F, Yuan CS. Colon cancer chemopreventive effects of baicalein, an active enteric microbiome metabolite from baicalin. Int J Oncol. 2015;47(5):1749–58. doi:10.3892/ijo.2015.3173.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. de Oliveira MR, Nabavi SF, Habtemariam S, Erdogan Orhan I, Daglia M, Nabavi SM. The effects of baicalein and baicalin on mitochondrial function and dynamics: a review. Pharmacol Res. 2015;100:296–308. doi:10.1016/j.phrs.2015.08.021.

    Article  PubMed  Google Scholar 

  7. Kotani A, Kojima S, Hakamata H, Kusu F. HPLC with electrochemical detection to examine the pharmacokinetics of baicalin and baicalein in rat plasma after oral administration of a Kampo medicine. Anal Biochem. 2006;350(1):99–104. doi:10.1016/j.ab.2005.11.007.

    Article  CAS  PubMed  Google Scholar 

  8. Huang Y, Tsang SY, Yao X, Chen ZY. Biological properties of baicalein in cardiovascular system. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5(2):177–84.

    Article  CAS  PubMed  Google Scholar 

  9. Teng Y, Nian H, Zhao H, Chen P, Wang G. Biotransformation of baicalin to baicalein significantly strengthens the inhibition potential towards UDP-glucuronosyltransferases (UGTs) isoforms. Pharmazie. 2013;68(9):763–7.

    CAS  PubMed  Google Scholar 

  10. Wang F, Chen H, Yan Y, Liu Y, Zhang S, Liu D. Baicalein protects against the development of angiotensin II-induced abdominal aortic aneurysms by blocking JNK and p38 MAPK signaling. Sci China Life Sci. 2016;. doi:10.1007/s11427-015-0277-8.

    Google Scholar 

  11. Wang J, Luo H, Yang L, Li Y. Baicalein induces apoptosis and reduces inflammation in LPS-stimulated keratinocytes by blocking the activation of NF-kappaB: implications for alleviating oral lichen planus. Cell Mol Biol (Noisy-le-grand). 2016;62(7):55–60.

    CAS  Google Scholar 

  12. Zhang Y, Song L, Cai L, Wei R, Hu H, Jin W. Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells. Food Chem Toxicol. 2013;53:325–33. doi:10.1016/j.fct.2012.12.019.

    Article  CAS  PubMed  Google Scholar 

  13. Patwardhan RS, Sharma D, Thoh M, Checker R, Sandur SK. Baicalein exhibits anti-inflammatory effects via inhibition of NF-kappaB transactivation. Biochem Pharmacol. 2016;108:75–89. doi:10.1016/j.bcp.2016.03.013.

    Article  CAS  PubMed  Google Scholar 

  14. Chen H, Gao Y, Wu J, Chen Y, Chen B, Hu J, et al. Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies. Cancer Lett. 2014;354(1):5–11. doi:10.1016/j.canlet.2014.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Schreiner F, El-Maarri O, Gohlke B, Stutte S, Nuesgen N, Mattheisen M, et al. Association of COMT genotypes with S-COMT promoter methylation in growth-discordant monozygotic twins and healthy adults. BMC Med Genet. 2011;12:115. doi:10.1186/1471-2350-12-115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang J, Kulik HJ, Martinez TJ, Klinman JP. Mediation of donor–acceptor distance in an enzymatic methyl transfer reaction. Proc Natl Acad Sci USA. 2015;112(26):7954–9. doi:10.1073/pnas.1506792112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mannisto PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev. 1999;51(4):593–628.

    CAS  PubMed  Google Scholar 

  18. Murphy BC, O’Reilly RL, Singh SM. Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2005;133B(1):37–42. doi:10.1002/ajmg.b.30134.

    Article  PubMed  Google Scholar 

  19. He YQ, Liu Y, Zhang BF, Liu HX, Lu YL, Yang L, et al. Identification of the UDP-glucuronosyltransferase isozyme involved in senecionine glucuronidation in human liver microsomes. Drug Metab Dispos. 2010;38(4):626–34. doi:10.1124/dmd.109.030460.

    Article  CAS  PubMed  Google Scholar 

  20. Ebner T, Remmel RP, Burchell B. Human bilirubin UDP-glucuronosyltransferase catalyzes the glucuronidation of ethinylestradiol. Mol Pharmacol. 1993;43(4):649–54.

    CAS  PubMed  Google Scholar 

  21. Lu Y, Zhu J, Chen X, Li N, Fu F, He J, et al. Identification of human UDP-glucuronosyltransferase isoforms responsible for the glucuronidation of glycyrrhetinic acid. Drug Metab Pharmacokinet. 2009;24(6):523–8.

    Article  CAS  PubMed  Google Scholar 

  22. Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet. 2015;30(1):30–51. doi:10.1016/j.dmpk.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  23. Tukey RH, Strassburg CP. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Mol Pharmacol. 2001;59(3):405–14.

    CAS  PubMed  Google Scholar 

  24. Bock KW. Roles of human UDP-glucuronosyltransferases in clearance and homeostasis of endogenous substrates, and functional implications. Biochem Pharmacol. 2015;96(2):77–82. doi:10.1016/j.bcp.2015.04.020.

    Article  CAS  PubMed  Google Scholar 

  25. Ritter JK. Intestinal UGTs as potential modifiers of pharmacokinetics and biological responses to drugs and xenobiotics. Expert Opin Drug Metab Toxicol. 2007;3(1):93–107. doi:10.1517/17425255.3.1.93.

    Article  CAS  PubMed  Google Scholar 

  26. Ritter JK. Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact. 2000;129(1–2):171–93.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang L, Lin G, Zuo Z. Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein. Pharm Res. 2007;24(1):81–9. doi:10.1007/s11095-006-9126-y.

    Article  PubMed  Google Scholar 

  28. Zhu X, Deng J, Zuo Z, Lam TN. An agent-based approach to dynamically represent the pharmacokinetic properties of baicalein. AAPS J. 2016;. doi:10.1208/s12248-016-9955-5.

    Google Scholar 

  29. Xing J, Chen X, Zhong D. Absorption and enterohepatic circulation of baicalin in rats. Life Sci. 2005;78(2):140–6. doi:10.1016/j.lfs.2005.04.072.

    Article  CAS  PubMed  Google Scholar 

  30. Moghaddam E, Teoh BT, Sam SS, Lani R, Hassandarvish P, Chik Z, et al. Baicalin, a metabolite of baicalein with antiviral activity against dengue virus. Sci Rep. 2014;4:5452. doi:10.1038/srep05452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liang SC, Xia YL, Hou J, Ge GB, Zhang JW, He YQ, et al. Methylation, glucuronidation, and sulfonation of daphnetin in human hepatic preparations in vitro: metabolic profiling, pathway comparison, and bioactivity analysis. J Pharm Sci. 2016;105(2):808–16. doi:10.1016/j.xphs.2015.10.010.

    Article  CAS  PubMed  Google Scholar 

  32. Jiang L, Liang SC, Wang C, Ge GB, Huo XK, Qi XY, et al. Identifying and applying a highly selective probe to simultaneously determine the O-glucuronidation activity of human UGT1A3 and UGT1A4. Sci Rep. 2015;5:9627. doi:10.1038/srep09627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cui Y, Tian X, Ning J, Wang C, Yu Z, Wang Y, et al. Metabolic profile of 3-acetyl-11-keto-beta-boswellic acid and 11-keto-beta-boswellic acid in human preparations in vitro, species differences, and bioactivity variation. AAPS J. 2016;. doi:10.1208/s12248-016-9945-7.

    PubMed  Google Scholar 

  34. Tian X, Liang S, Wang C, Wu B, Ge G, Deng S, et al. Erratum to: Regioselective glucuronidation of and rographolide and its major derivatives: metabolite identification, isozyme contribution, and species differences. AAPS J. 2015;17(2):479. doi:10.1208/s12248-014-9683-7.

    Article  PubMed  Google Scholar 

  35. Zhu L, Ge G, Liu Y, He G, Liang S, Fang Z, et al. Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9. Xenobiotica. 2012;42(10):1001–8. doi:10.3109/00498254.2012.681814.

    Article  CAS  PubMed  Google Scholar 

  36. Han DH, Lee Y, Ahn JH. Biological synthesis of baicalein derivatives using Escherichia coli. J Microbiol Biotechnol. 2016;. doi:10.4014/jmb.1605.05050.

    Google Scholar 

  37. Li J, Wang YH, Smillie TJ, Khan IA. Identification of phenolic compounds from Scutellaria lateriflora by liquid chromatography with ultraviolet photodiode array and electrospray ionization tandem mass spectrometry. J Pharm Biomed Anal. 2012;63:120–7. doi:10.1016/j.jpba.2012.01.027.

    Article  CAS  PubMed  Google Scholar 

  38. Qiao X, Li R, Song W, Miao WJ, Liu J, Chen HB, et al. A targeted strategy to analyze untargeted mass spectral data: rapid chemical profiling of Scutellaria baicalensis using ultra-high performance liquid chromatography coupled with hybrid quadrupole orbitrap mass spectrometry and key ion filtering. J Chromatogr A. 2016;1441:83–95. doi:10.1016/j.chroma.2016.02.079.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Second Affiliated Hospital of Dalian Medical University, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Lvshunkou District, Dalian, 116044, China

    Ruiya Zhang, Yonglei Cui, Yan Wang, Xiaokui Huo, Chao Wang, BaoJing Zhang, Xiaobo Wang & Zhonghui Yu

  2. College of Basic Medical Science, Dalian Medical University, Dalian, China

    Xiangge Tian

  3. Shanghai Haini Pharmaceutical Co. Ltd., No. 3999, Hunan Road of Pudong New District, Shanghai, China

    Lu Zheng, HaiJian Cong & Bin Wu

  4. Department of Pharmacy and Traditional Chinese Medicine, Chinese People’s Liberation Army 210 Hospital, Shanghai, China

    Yan Wang & Xiaobo Wang

Authors
  1. Ruiya Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yonglei Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangge Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. HaiJian Cong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaokui Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. BaoJing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiaobo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Zhonghui Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZY, BW, and XT designed the experiments. RZ, YC, and XT performed the experiments. CW, XW, and YW analyzed the data. XH, HC, LZ, and BZ prepared the figures. ZY, XW, and RZ wrote the main text. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Xiangge Tian or Zhonghui Yu.

Ethics declarations

Funding

We thank the NSFC (81573324), Dalian Outstanding Youth Science and Technology Talent (2015J12JH201), and Innovation Team of Dalian Medical University for financial support.

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1904 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, R., Cui, Y., Wang, Y. et al. Catechol-O-Methyltransferase and UDP-Glucuronosyltransferases in the Metabolism of Baicalein in Different Species. Eur J Drug Metab Pharmacokinet 42, 981–992 (2017). https://doi.org/10.1007/s13318-017-0419-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-017-0419-9

Search

Navigation