Skip to main content
SpringerLink
Log in

A highly selective fluorescent probe for real-time imaging of UDP-glucuronosyltransferase 1A8 in living cells and tissues

  • Research Article
  • Published:
Frontiers of Chemical Science and Engineering Aims and scope Submit manuscript

Abstract

Uridine diphosphate (UDP)-glucuronosyl-transferases (UGTs) are enzymes involved in the biotransformation of important endogenous compounds such as steroids, bile acids, and hormones as well as exogenous substances including drugs, environmental toxicants, and carcinogens. Here, a novel fluorescent probe BDMP was developed based on boron-dipyrromethene (BODIPY) with high sensitivity for the detection of UGT1A8. The glucuronidation of BDMP not only exhibited a red-emission wavelength (λex/λem = 500/580 nm), but also displayed an excellent UGT1A8-dependent fluorescence signal with a good linear relationship with UGT1A8 concentration. Based on this perfect biocompatibility and cell permeability, BDMP was successfully used to image endogenous UGT1A8 in human cancer cell lines (LoVo and HCT15) in real time. In addition, BDMP could also be used to visualize UGT1A8 in tumor tissues. These results suggested that BDMP is a promising molecular tool for the investigation of UGT1A8-mediated physiological function in humans.

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

Similar content being viewed by others

References

  1. Tian X G, Liang S C, Wang C, Wu B J, Ge G B, Deng S, Liu K X, Yang L, Ma X C. Regioselective glucuronidation of andrographolide and its major derivatives: metabolite identification, isozyme contribution, and species differences. AAPS Journal, 2015, 17(1): 156–166

    Article  CAS  Google Scholar 

  2. Kiang T K, Ensom M H, Chang T K. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacology & Therapeutics, 2005, 106(1): 97132

    Article  Google Scholar 

  3. Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metabolism and Pharmacokinetics, 2015, 30(1): 30–51

    Article  CAS  PubMed  Google Scholar 

  4. Knights K M, Miners J O. Renal UDP-glucuronosyltransferases and the glucuronidation of xenobiotics and endogenous mediators. Drug Metabolism Reviews, 2010, 42(1): 63–73

    Article  CAS  PubMed  Google Scholar 

  5. Mu J, He L, Huang P, Chen X Y. Engineering of nanoscale coordination polymers with biomolecules for advanced applications. Coordination Chemistry Reviews, 2019, 399: 213039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Izukawa T, Nakajima M, Fujiwara R, Yamanaka H, Fukami T, Takamiya M, Aoki Y, Ikushiro S, Sakaki T, Yokoi T. Quantitative analysis of UDP-glucuronosyltransferase (UGT) 1A and UGT2B expression levels in human livers. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 2009, 37(8): 1759–1768

    Article  CAS  Google Scholar 

  7. Nakamura A, Nakajima M, Yamanaka H, Fujiwara R, Yokoi T. Expression of UGT1A and UGT2B mRNA in human normal tissues and various cell lines. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 2008, 36(8): 1461–1464

    Article  CAS  Google Scholar 

  8. Wu B J, Kulkarni K, Basu S, Zhang S X, Hu M. First-pass metabolism via UDP-glucuronosyltransferase: a barrier to oral bioavailability of phenolics. Journal of Pharmaceutical Sciences, 2011, 100(9): 3655–3681

    Article  CAS  PubMed  Google Scholar 

  9. Mackenzie P I, Bock K W, Burchell B, Guillemette C, Ikushiro S, Iyanagi T, Miners J O, Owens I S, Nebert D W. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenetics and Genomics, 2005, 15(10): 677–685

    Article  CAS  PubMed  Google Scholar 

  10. Sanchez-Dominguez C N, Gallardo-Blanco H L, Salinas-Santander M A, Ortiz-Lopez R. Uridine 5′-diphospho-glucronosyltrasferase: its role in pharmacogenomics and human disease. Experimental and Therapeutic Medicine, 2018, 16(1): 3–11

    PubMed  PubMed Central  Google Scholar 

  11. Zhang R Y, Cui Y L, Wang Y, Tian X G, Zheng L, Cong H J, Wu B, Huo X K, Wang C, Zhang B J, Wang X, Yu Z. Catechol-O-methyltransferase and UDP-glucuronosyltransferases in the metabolism of baicalein in different species. European Journal of Drug Metabolism and Pharmacokinetics, 2017, 42(6): 981–992

    Article  CAS  PubMed  Google Scholar 

  12. Xu M, Dong P P, Tian X G, Wang C, Huo X K, Zhang B J, Wu L J, Deng S, Ma X C. Drug interaction study of natural steroids from herbs specifically toward human UDP-glucuronosyltransferase (UGT) 1A4 and their quantitative structure activity relationship (QSAR) analysis for prediction. Pharmacological Research, 2016, 110: 139–150

    Article  CAS  PubMed  Google Scholar 

  13. de Boer Y S, Sherker A H. Herbal and dietary supplement—induced liver injury. Clinics in Liver Disease, 2017, 21(1): 135–149

    Article  PubMed  Google Scholar 

  14. Tukey R H, Strassburg C P. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annual Review of Pharmacology and Toxicology, 2000, 40(1): 581–616

    Article  CAS  PubMed  Google Scholar 

  15. Tukey R H, Strassburg C P. Genetic multiplicity of the human UDP-glucuronosyltransferases and regulation in the gastrointestinal tract. Molecular Pharmacology, 2001, 59(3): 405–414

    Article  CAS  PubMed  Google Scholar 

  16. Lehmann L, Wagner J. Gene expression of 17β-estradiol-metabolizing isozymes: comparison of normal human mammary gland to normal human liver and to cultured human breast adenocarcinoma cells. Advances in Experimental Medicine and Biology, 2008, 617: 617–624

    Article  CAS  PubMed  Google Scholar 

  17. Zhao F, Wang X, Wang Y, Zhang J B, Lai R, Zhang B, Zhou X Y. The function of uterine UDP-glucuronosyltransferase 1A8 (UGT1A8) and UDP-glucuronosyltransferase 2B7 (UGT2B7) is involved in endometrial cancer based on estrogen metabolism regulation. Hormones (Athens, Greece), 2020, 19(3): 403–412

    Article  Google Scholar 

  18. Tian X G, Yan F, Zheng J Y, Cui X L, Feng L, Li S, Jin L L, James T D, Ma X C. Endoplasmic reticulum targeting ratiometric fluorescent probe for carboxylesterase 2 detection in drug-induced acute liver injury. Analytical Chemistry, 2019, 91(24): 15840–15845

    Article  CAS  PubMed  Google Scholar 

  19. Tian X G, Liu T, Li L, Shao B, Yao D H, Feng L, Cui J N, James T D, Ma X C. Visual high-throughput screening for developing a fatty acid amide hydrolase natural inhibitor based on an enzyme-activated fluorescent probe. Analytical Chemistry, 2020, 92(14): 9493–9500

    Article  CAS  PubMed  Google Scholar 

  20. Wang Y, Yu F B, Luo X Z, Li M S, Zhao L L, Yu F B. Visualization of carboxylesterase 2 with a near-infrared two-photon fluorescent probe and potential evaluation of its anticancer drug effects in an orthotopic colon carcinoma mice model. Chemical Communications, 2020, 56(32): 4412–4415

    Article  CAS  PubMed  Google Scholar 

  21. Yang Y, Zhou T T, Jin M, Zhou K Y, Liu D D, Li X, Huo F J, Li W, Yin C X. Thiol-chromene “click” reaction triggered self-immolative for NIR visualization of thiol flux in physiology and pathology of living cells and mice. Journal of the American Chemical Society, 2020, 142(3): 1614–1620

    Article  CAS  PubMed  Google Scholar 

  22. Li H Y, Liu Y, Li X Y, Li X H, Ma H M. Design, synthesis and application of a dual-functional fluorescent probe for reactive oxygen species and viscosity. Spectrochimica Acta. Part A: Molecular and Biomolecular Spectroscopy, 2021, 246: 119059

    Article  CAS  Google Scholar 

  23. Gurram B, Li M, Fan J L, Wang J Y, Peng X J. Near-infrared fluorescent probe for fast track of cyclooxygenase-2 in Golgi apparatus in cancer cells. Frontiers of Chemical Science and Engineering, 2020, 14(1): 41–52

    Article  CAS  Google Scholar 

  24. Xu S Y, Sedgwick A C, Elfeky S A, Chen W B, Jones A S, Williams G T, Jenkins A T A, Bull S D, Fossey J S, James T D. A boronic acid-based fluorescent hydrogel for monosaccharide detection. Frontiers of Chemical Science and Engineering, 2020, 14(1): 112–116

    Article  CAS  Google Scholar 

  25. Liu T, Tian M M, Wang J Y, Tian X G, Liu J H, Feng L, Ma X C, Cui J N. Rational design of a fluorescent probe for the detection of LAP and its application in drug-induced liver injury. Spectrochimica Acta. Part A: Molecular and Biomolecular Spectroscopy, 2021, 251: 119362

    Article  CAS  Google Scholar 

  26. Liu H W, Chen L L, Xu C Y, Li Z, Zhang H Y, Zhang X B, Tan W H. Recent progresses in small-molecule enzymatic fluorescent probes for cancer imaging. Chemical Society Reviews, 2018, 47 (18): 7140–7180

    Article  CAS  PubMed  Google Scholar 

  27. Zhang J J, Chai X Z, He X P, Kim H J, Yoon J, Tian H. Fluorogenic probes for disease-relevant enzymes. Chemical Society Reviews, 2019, 48(2): 683–722

    Article  CAS  PubMed  Google Scholar 

  28. Wu X F, Shi W, Li X H, Ma H M. Recognition moieties of small molecular fluorescent probes for bioimaging of enzymes. Accounts of Chemical Research, 2019, 52(7): 1892–1904

    Article  CAS  PubMed  Google Scholar 

  29. Ning J, Liu T, Dong P P, Wang W, Ge G B, Wang B, Yu Z L, Shi L, Tian X G, Huo X K, et al. Molecular design strategy to construct the near-infrared fluorescent probe for selectively sensing human cytochrome P450 2J2. Journal of the American Chemical Society, 2019, 141(2): 1126–1134

    Article  CAS  PubMed  Google Scholar 

  30. Liu Z P, Sun Q. A near-infrared fluorescent probe for imaging of nitroxyl in living cells. Spectrochimica Acta. Part A: Molecular and Biomolecular Spectroscopy, 2020, 241: 118680

    Article  CAS  Google Scholar 

  31. Ning J, Wang W, Ge G B, Chu P, Long F D, Yang Y L, Peng Y L, Feng L, Ma X C, James T D. Target enzyme-activated two-photon fluorescent probes: a case study of CYP3A4 using a two-dimensional design strategy. Angewandte Chemie International Edition, 2019, 58(29): 9959–9963

    Article  CAS  PubMed  Google Scholar 

  32. Feng L, Ning J, Tian X G, Wang C, Zhang L, Ma X C, James T D. Fluorescent probes for bioactive detection and imaging of phase II metabolic enzymes. Coordination Chemistry Reviews, 2019, 399: 213026

    Article  CAS  Google Scholar 

  33. Ma H M. Spectroscopic Probes and Sensing Analysis. Beijing: Chemical Industry Press, 2020 (in Chinese)

    Google Scholar 

  34. Feng L, Ning J, Tian X G, Wang C, Yu Z L, Huo X K, Xie T, Zhang B J, James T D, Ma X C. Fluorescent probes for the detection and imaging of cytochrome P450. Coordination Chemistry Reviews, 2021, 437: 213740

    Article  CAS  Google Scholar 

  35. Feng L, Tian Z H, Zhang M, He X, Tian X G, Yu Z L, Ma X C, Wang C. Real-time identification of gut microbiota with amino-peptidase N using an activable NIR fluorescent probe. Chinese Chemical Letters, 2021, https://doi.org/10.1016/j.cclet.2021.03.056

  36. Terai T, Tomiyasu R, Ota T, Ueno T, Komatsu T, Hanaoka K, Urano Y, Nagano T. TokyoGreen derivatives as specific and practical fluorescent probes for UDP-glucuronosyltransferase (UGT) 1A1. Chemical Communications, 2013, 49(30): 3101–3103

    Article  CAS  PubMed  Google Scholar 

  37. Lv X, Feng L, Ai C Z, Hou J, Wang P, Zou L W, Cheng J, Ge G B, Cui J N, Yang L. A practical and high-affinity fluorescent probe for uridine diphosphate glucuronosyltransferase 1A1: a good surrogate for bilirubin. Journal of Medicinal Chemistry, 2017, 60(23): 9664–9675

    Article  CAS  PubMed  Google Scholar 

  38. Kim B, Fukuda M, Lee J Y, Su D, Sanu S, Silvin A, Khoo A T T, Kwon T, Liu X, Chi W, Liu X, Choi S, Wan D S Y, Park S J, Kim J S, Ginhoux F, Je H S, Chang Y T. Visualizing microglia with a fluorescence turn-on Ugt1a7c substrate. Angewandte Chemie International Edition, 2019, 58(24): 7972–7976

    Article  CAS  PubMed  Google Scholar 

  39. Lee J S, Kang N Y, Kim Y K, Samanta A, Feng S, Kim H K, Vendrell M, Park J H, Chang Y T. Synthesis of a BODIPY library and its application to the development of live cell glucagon imaging probe. Journal of the American Chemical Society, 2009, 131(29): 10077–10082

    Article  CAS  PubMed  Google Scholar 

  40. Huang Y P, Cao Y F, Fang Z Z, Zhang Y Y, Hu C M, Sun X Y, Yu Z W, Zhu X, Hong M, Yang L, Sun H Z. Glycyrrhetinic acid exhibits strong inhibitory effects towards UDP-glucuronosyltransferase (UGT) 1A3 and 2B7. Phytotherapy Research, 2013, 27(9): 1358–1361

    Article  CAS  PubMed  Google Scholar 

  41. Zhu L L, Ge G B, Liu Y, He G Y, Liang S C, Fang Z Z, Dong P P, Cao Y F, Yang L. Potent and selective inhibition of magnolol on catalytic activities of UGT1A7 and 1A9. Xenobiotica, 2012, 42(10): 1001–1008

    Article  CAS  PubMed  Google Scholar 

  42. He Y Q, Liu Y, Zhang B F, Liu H X, Lu Y L, Yang L, Xiong A Z, Xu L L, Wang C H, Yang L, Wang Z T. Identification of the UDP-glucuronosyltransferase isozyme involved in senecionine glucuronidation in human liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 2010, 38(4): 626–634

    Article  CAS  Google Scholar 

  43. Sahai J, Gallicano K, Pakuts A, Cameron D W. Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. Journal of Infectious Diseases, 1994, 169 (5): 1103–1107

    Article  CAS  Google Scholar 

  44. Yan F, Cui Y L, An Y, Ning J, Zhao X Y, Feng L, Huo X K, Wang C, Lv C Z, Ma X C, Tian X. A dual functional probe for assessing human CYP450 3A5 and 3A enzymes bioactivities. Future Medicinal Chemistry, 2019, 11(22): 2891–2903

    Article  CAS  PubMed  Google Scholar 

  45. Tian X G, Huo X K, Dong P P, Wu B J, Wang X B, Wang C, Liu K X, Ma X C. Sulfation of melatonin: enzymatic characterization, differences of organs, species and genders, and bioactivity variation. Biochemical Pharmacology, 2015, 94(4): 282–296

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Natural Science Foundation of Liaoning Province 2020-MS-252 and the National Key R&D Program of China (Grant No. 2018YFC1603001).

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy, School of Medicine, Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Hangzhou Normal University, Hangzhou, 311121, China

    Mingyue Zhu & Lei Feng

  2. Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention, College of Pharmacy, College of Integrative Medicine, Dalian Medical University, Dalian, 116044, China

    Mingyue Zhu, Lingling Jin, Xiaokui Huo, Chao Wang, Yan Tian, Xiangge Tian & Lei Feng

  3. School of Life Sciences, Northwestern Polytechnical University, Xi’an, 710072, China

    Zhenhao Tian

  4. State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, 116024, China

    Jingnan Cui

Authors
  1. Mingyue Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenhao Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingling Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaokui Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jingnan Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiangge Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lei Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yan Tian, Xiangge Tian or Lei Feng.

Ethics declarations

Declaration of competing interest All the authors declare no competing financial interest.

Electronic Supplementary Material

11705_2021_2064_MOESM1_ESM.pdf

A highly selective fluorescent probe for real-time imaging of UDP-glucuronosyltransferase 1A8 in living cells and tissues

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhu, M., Tian, Z., Jin, L. et al. A highly selective fluorescent probe for real-time imaging of UDP-glucuronosyltransferase 1A8 in living cells and tissues. Front. Chem. Sci. Eng. 16, 103–111 (2022). https://doi.org/10.1007/s11705-021-2064-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11705-021-2064-8

Keywords

Search

Navigation