Skip to main content
SpringerLink
Log in

Acyl glucuronides–mediators of drug-induced toxicities?

  • Review Article
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

The role of acyl glucuronide (AG) metabolites as mediators of drug-induced toxicities remains controversial, in part due to difficulties in studying this group of reactive drug conjugates. Confounding factors include the bioactivation of carboxylic acid drugs by alternative pathways, AG-mediated inhibition of key enzymes and transporters, and unanticipated interactions with several biological systems. These issues, together with the inherent instability of AGs under physiological conditions, have led to significant challenges in assessing the human safety of AGs according to current regulatory guidances. Despite important advances in the analytical methodology used to detect, identify and quantify AGs in biological fluids and tissues, there is a lack of information on the molecular mechanisms that underlie the toxicity of carboxylic acid-containing drugs and their AG metabolites. This review summarizes the current status of the field, and the de-risking strategies that have been adopted to minimize the likelihood of AG-mediated toxicity in drug discovery and lead optimization programs.

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
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

AG:

acyl glucuronide

acyl-CoA:

acyl coenzyme A thioester

acyl-SG:

glutathione thioester

CoASH:

coenzyme A

DILI:

drug-induced liver injury

GSH:

glutathione

MIST:

metabolites in safety testing

NSAID:

nonsteroidal anti-inflammatory drug

PPAR:

peroxisome proliferator-activated receptor

UGT:

uridine-5’-diphosphoglucuronosyl-transferase.

References

  1. Baba A, Yoshioka T. Structure-activity relationships for degradation reaction of 1-β-O-acyl glucuronides: kinetic description and prediction of intrinsic electrophilic reactivity under physiological conditions. Chem Res Toxicol. 2009;22:158–72. https://doi.org/10.1021/tx800292m.

    Article  CAS  PubMed  Google Scholar 

  2. Camilleri P, Buch A, Soldo B, Hutt AJ. The influence of physicochemical properties on the reactivity and stability of acyl glucuronides. Xenobiotica. 2018;48:958–72. https://doi.org/10.1080/00498254.2017.1384967.

    Article  CAS  PubMed  Google Scholar 

  3. Stachulski AV, Harding JR, Lindon JC, Maggs JL, Park BK, Wilson ID. Acyl glucuronides: biological activity, chemical reactivity, and chemical synthesis. J Med Chem. 2006;49:6931–45. https://doi.org/10.1021/jm060599z.

    Article  CAS  PubMed  Google Scholar 

  4. Skonberg C, Olsen J, Madsen KG, Hansen SH, Grillo MP. Metabolic activation of carboxylic acids. Expert Opin Drug Metab Toxicol. 2008;4:425–38. https://doi.org/10.1517/17425255.4.4.425.

    Article  CAS  PubMed  Google Scholar 

  5. Acharya AS, Sussman LG. The reversibility of the ketoamide linkages of aldoses with proteins. J Biol Chem. 1984;259:4372–8.

    Article  CAS  PubMed  Google Scholar 

  6. Benet LZ, Spahn-Langguth H, Iwakawa S, Volland C, Mizuma T, Mayer S, Lin ET. Predictability of the covalent binding of acidic drugs in man. Life Sci. 1993;53:PL141–146.

    Article  CAS  PubMed  Google Scholar 

  7. Boelsterli UA. Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions. Curr Drug Metab. 2002;5:439–50.

    Article  Google Scholar 

  8. Regan SL, Maggs JL, Hammond TG, Lambert C, Williams DP, Park BK. Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos. 2010;31:367–95. https://doi.org/10.1002/bdd.720.

    Article  CAS  PubMed  Google Scholar 

  9. Sawamura R, Okudaira, Watanabe K, Murai T, Kobayashi Y, Tachibana M, Ohnuki T, Masuda K, Honma H, Kurihara A, Okazaki O. Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical instability of acyl glucuronide. Drug Metab Dispos. 2010;38:1857–64. https://doi.org/10.1124/dmd.110.034173.

    Article  CAS  PubMed  Google Scholar 

  10. Jinno N, Ohashi S, Tagashira M, Kohira T, Yamada S. A simple method to evaluate reactivity of acylglucuronides optimized for early stage drug discovery. Biol Pharm Bull. 2013;36:1509–13.

    Article  CAS  PubMed  Google Scholar 

  11. Zhong S, Jones R, Lu W, Schadt S, Ottaviani G. A new rapid in vitro assay for assessing reactivity of acyl glucuronides. Drug Metab Dispos. 2015;43:1711–7. https://doi.org/10.1124/dmd.115.066159.

    Article  CAS  PubMed  Google Scholar 

  12. Seitz S, Boelsterli UA. Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats. Gastroenterol. 1998;115:1476–82.

    Article  CAS  Google Scholar 

  13. Iwamura A, Watanabe K, Akai S, Nishinosono T, Tsuneyama K, Oda S, Kume T, Yokoi T Zomepirac acyl glucuronide is responsible for zomepirac-induced acute liver injury in mice. 2016;44:888-96. https://doi.org/10.1124/dmd.116.069575.

  14. Oda S, Shirai Y, Akai S, Nakajima S, Tsuneyama K, Yokoi T. Toxocological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice. J Appl Toxicol. 2017;37:545–53. https://doi.org/10.1002/jat.3388.

    Article  CAS  PubMed  Google Scholar 

  15. Kalgutkar AS. Designing around structural alerts in drug discovery. J Med Chem. 2020;63:6276–302. https://doi.org/10.1021/acs.jmedchem.9b00917.

    Article  CAS  PubMed  Google Scholar 

  16. Hammond TG, Meng X, Jenkins RE, Maggs JL, Castelazo AS, Regan SL, Bennett SNL, Earnshaw CJ, Aithal GP, Pande I, Kenna JG, Stachulski AV, Park BK, Williams DP. Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients. J Pharm Exp Ther. 2014;350:387–402. https://doi.org/10.1124/jpet.114.215079.

    Article  Google Scholar 

  17. Bradshaw PR, Athersuch TJ, Stachulski AV, Wilson ID. Acyl glucuronide reactivity in perspective. Drug Disco Today. 2020;25:1639–50. https://doi.org/10.1016/j.drudis.2020.07.009.

    Article  CAS  Google Scholar 

  18. Darnell M, Breitholz K, Isin EM, Jurva U, Weidolf L. Significantly different covalent binding of oxidative metabolites, acyl glucuronides, and S-acyl CoA conjugates formed from xenobiotic carboxylic acids in human liver microsomes. Chem Res Toxicol. 2015;28:886–96. https://doi.org/10.1021/tx500514z.

    Article  CAS  PubMed  Google Scholar 

  19. Grillo MP, Benet LZ. Studies of the reactivity of clofibryl-S-acyl-CoA thioester with glutathione in vitro. Drug Metab Dispos. 2002;30:55–62.

    Article  CAS  PubMed  Google Scholar 

  20. Grillo, MP Drug-S-acyl-glutathione thioesters: synthesis, bioanalytical properties, chemical reactivity, biological formation and degradation. 2011;12:229–44.

  21. Darnell M, Weidolf L. Metabolism of xenobiotic carboxylic acids: focus on coenzyme A conjugation, reactivity, and interference with lipid metabolism. Chem Res Toxicol. 2013;26:1139–55. https://doi.org/10.1021/tx400183y.

    Article  CAS  PubMed  Google Scholar 

  22. Mitra K. Acyl glucuronide and coenzyme A thioester metabolites of carboxylic acid-containing drug molecules: layering chemistry with reactive metabolism and toxicology. Chem Res Toxicol. 2022;35:1777–88. https://doi.org/10.1021/acs.chemrestox.2c00188.

    Article  CAS  PubMed  Google Scholar 

  23. Shang J, Tschirret-Guth R, Cancilla M, Samuel K, Chen Q, Chobanian HR, Thomas A, Tong W, Josien H, Buevich AV, Mitra K. Bioactivation of GPR40 agonist MK-8666: formation of protein adducts in vitro from reactive acyl glucuronide and acyl CoA thioester. Chem Res Toxicol. 2020;33:191–201. https://doi.org/10.1021/acs.chemrestox.9b00226.

    Article  CAS  PubMed  Google Scholar 

  24. Boelsterli UA. Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity. Toxicol Appl Pharm. 2003;192:307–22. https://doi.org/10.1016/S0041-008X(03)00368-5.

    Article  CAS  Google Scholar 

  25. Tang W. The metabolism of diclofenac – enzymology and toxicology perspective. Curr Drug Metab. 2003;4:319–29. https://doi.org/10.2174/1389200033489398.

    Article  CAS  PubMed  Google Scholar 

  26. Grillo MP. A novel bioactivation pathway for 2-[2-(2,6-dichlorophenyl)aminophenyl]ethanoic acid (diclofenac) initiated by cytochrome P450-mediated oxidative decarboxylation. Drug Metab Dispos. 2008;36:1740–4.

  27. Driscoll JP, Yadav AS, Shah NR. Role of glucuronidation and P450 oxidation in the bioactivation of bromfenac. Drug Metab Dispos. 2018;31:223–30. https://doi.org/10.1021/acs.chemresyox.7b00293.

    Article  CAS  Google Scholar 

  28. Chen Q, Doss GA, Tung EC, Liu W, Tang YS, Braun MP, Didolkar V, Strauss JR, Wang RW, Stearns RA, Evans DC, Baillie TA, Tang W. Evidence for the bioactivation of zomepirac and tolmetin by an oxidative pathway: identification of glutathione adducts in vitro in human liver microsomes and in vivo in rats. Drug Metab Dispos. 2006;34:1456–151. https://doi.org/10.1124/dmd.106.004341.

    Article  Google Scholar 

  29. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1: SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharm Exp Ther. 2004;311:228–36. https://doi.org/10.1124/jpet.104.068536.

    Article  CAS  Google Scholar 

  30. Ogilvie BW, Zhang D, Li W, Rodrigues AD, Gipson AE, Holsapple J, Toren P, Parkinson A. Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions. Drug Metab Dispos. 2006;34:191–7. https://doi.org/10.1124/dmd.105.007633.

    Article  CAS  PubMed  Google Scholar 

  31. Baer BR, DeLisle RK, Allen A. Benzylic oxidation of gemfibrozil-1-O-β-glucuronide by P450 2C8 leads to heme alkylation and irreversible inhibition. Chem Res Toxicol. 2009;22:1298–309. https://doi.org/10.1021/tx900105n.

    Article  CAS  PubMed  Google Scholar 

  32. Torino A, Filppula AM, Kailari O, Neuvonen M, Nyrönen TH, Tapaninen T, Neuvonen, Niemi M, Backman JT Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions. 2014;96:498-507. https://doi.org/10.1038/clpt.2014.141.

  33. Kahama H, Aurinsalo L, Neuvonen M, Katajamäki J, Paludetto MN, Viinamäki J, Launiainen T, Filppula AM, Torino A, Niemi M, Backman JY. An automated cocktail method for in vitro assessment of direct and time-dependent inhibition of nine major cytochrome P450 enzymes – application to establishing CYP2C8 inhibitor selectivity. Eur J Pharma Sci. 2021;162:105810 https://doi.org/10.1016/j.ejps.2021.105810.

    Article  Google Scholar 

  34. Zhang Y, Han Y-H, Putluru SP, Matta MK, Kole P, Mandlekar S, Furlong MT, Liu T, Iyer RA, Marathe P, Yang Z, Lai Y, Rodrigues AD. Diclofenac and its acyl glucuronide: determination of in vivo exposure in human subjects and characterization as human drug transporter substrates in vitro. Drug Metab Dispos. 2016;44:320–8. https://doi.org/10.1124/dmd.115.066944.

    Article  CAS  PubMed  Google Scholar 

  35. Tornio A, Neuvonen PJ, Niemi M, Backman JT. Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters. Expert Opin Drug Metab Toxicol. 2017;13:83–95. https://doi.org/10.1080/17425255.2016.1227791.

    Article  CAS  PubMed  Google Scholar 

  36. Iwaki M, Shimada H, Irino Y, Take M, Egashira S. Inhibition of methotrexate uptake via organic anion transporters OAT1 and OAT3 by glucuronides of nonsteroidal anti-inflammatory drugs. Biol Pharm Bull. 2017;40:926–31.

    Article  CAS  PubMed  Google Scholar 

  37. Katsube Y, Tsujimoto M, Koide H, Hira D, Ikeda I, Minegaki T, Morita S, Terada T, Nishiguchi K. In vitro evidence of potential interactions between CYP2C8 and candesartan acyl-β-D-glucuronide in the liver. Drug Metab Dispos. 2021;49:289–97. https://doi.org/10.1124/dmd.120.000126.

    Article  CAS  PubMed  Google Scholar 

  38. Järvinen E, Deng F, Kiander W, Sinokki A, Kidron H, Sjöstedt N. The role of uptake and efflux transporters in the disposition of glucuronide and sulfate conjugates. Front Pharm. 2022;12:802539 https://doi.org/10.3389/fpher.2021.802539.

    Article  Google Scholar 

  39. Tang LWT, Cheong TWH, Chan ECY. Febuxostat and its major acyl glucuronide metabolite are potent inhibitors of organic ion transporter 3: implications for drug-drug interactions with rivaroxaban. Biopharm Drug Dispos. 2022;43:57–65. https://doi.org/10.1002/bdd.2310.

    Article  CAS  PubMed  Google Scholar 

  40. Zameck-Gliszczynski MJ, Chu X, Polli, Paine MF, Galetin A. Understanding the transporter properties of metabolites: case studies and considerations for drug development. Drug Metab Disp. 2014;42:650–64. https://doi.org/10.1124/dmd.113.055558.

    Article  Google Scholar 

  41. Otieno MA, Snoeys J, Lam W, Ghosh A, Player MR, Pocai A, Salter R, Simic D, Skaggs H, Singh B, Lim H-K. Fasiglifam (TAK-875): mechanistic investigation and retrospective identification of hazards for drug induced liver injury. Toxicol Sci. 2018;163:374–84. https://doi.org/10.1093/toxsci/kfx040.

    Article  CAS  PubMed  Google Scholar 

  42. Ackerson T, Amberg A, Atzrodt J, Arabeyre C, Defossa E, Dorau M, Dudda A, Dwyer J, Holla W, Kissner T, Kohlmann M, Kürzel U, Pánczél J, Rajanna S, Riedel J, Schmist F, Wase K, Weitz D, Derdau V. Mechanistic investigations of the liver toxicity of the free fatty acid receptor 1 agonist fasiglifam (TAK875) and its primary metabolites. J Biochem Mol Toxicol. 2019;33:e22345 https://doi.org/10.1002/jbt.22345.

    Article  PubMed  Google Scholar 

  43. Ryder TF, Calabrese MF, Walker GS, Cameron KO, Reyes AR, Borzilleri KA, Delmore J, Miller R, Kurumbail RG, Ward J, Kung DW, Brown JA, Edmonds DJ, Eng H, Wolford AC, Kalgutkar AS. Acyl glucuronide metabolites of 6-chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid (PF-06409577) and related indole-3-carboxylic acid derivativesare direct activators of adenosine monophosphate-activated protein kinase (AMPK).J Med Chem. 2018;61:7273–-88.

  44. De Logu F, Puma SL, Landini L, Tuccinardi T, Poli G, Preti D, De Siena G, Patacchini R, Tsagareli MG, Geppetti P, Nassini R. The acyl-glucuronide metabolite of ibuprofen has analgesic and anti-inflammatory effects via the TRPA1 channel. Pharm Res. 2019;142:127–39. https://doi.org/10.1016/j.phrs.2019.02.019.

    Article  Google Scholar 

  45. Ma Y, Fu Y, Khojasteh SC, Dalvie D, Zhang D. Glucuronides as potential anionic substrates of human cytochrome P450 2C8 (CYP2C8). J Med Chem. 2017;60:8691–705. https://doi.org/10.1021/acs.jmedchem.7b00510.

    Article  CAS  PubMed  Google Scholar 

  46. Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu S-HL, Evans DC, Baillie TA. Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: role of acyl glucuronidation and sequential oxidative metabolism of the acyl glucuronide. J Pharm Exp Ther. 2002;303:969–78. https://doi.org/10.1124/jpet.102.038992.

    Article  CAS  Google Scholar 

  47. Nishihara M, Sudo M, Kawaguchi N, Takahashi J, Kiyota Y, Kondo T, Asahi S. An unusual metabolic pathway of sipoglitazar, a novel antidiabetic agent: cytochrome P450-catalyzed oxidation of sipoglitazar acyl glucuronide. Drug Metab Dispos. 2012;40:249–58. https://doi.org/10.1124/dmd.111.040105.

    Article  CAS  PubMed  Google Scholar 

  48. Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, Pearson PG, Baillie TA. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30:505–12.

    Article  CAS  PubMed  Google Scholar 

  49. Meng X, Maggs JL, Pryde DC, Planken S, Jenkins RE, Peakman TM, Beaumont K, Kohl C, Park BK, Stachulski AV. Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide: synthesis, reactivity, and mechanistic analysis. J Med Chem. 2007;50:6165–76. 10.1021.jm0706766.

    Article  CAS  PubMed  Google Scholar 

  50. Mulder T, Bobba S, Johnson K, Grandner JM, Wang W, Zhang C, Cai J, Choo EF, Khojasteh SC, Zhanf D. Bioactivation of α,β-unsaturated carboxylic acids through acyl glucuronidation. Drug Metab Dispos. 2020;48:819–29. https://doi.org/10.1124/dmd.120.000096.

    Article  CAS  PubMed  Google Scholar 

  51. Kassahun K, Hu P, Grillo MP, Davis MR, Jin L, Baillie TA. Metabolic activation of unsaturated derivatives of valproic acid. Identification of novel glutathione adducts formed through coenzyme A-dependent and -independent processes. Chem-Biol Interact. 1994;90:253–75.

    Article  CAS  PubMed  Google Scholar 

  52. Lewis DFV, Ioannides C, Parke DV. A retrospective study of the molecular toxicology of benoxaprofen. Toxicology. 1990;65:33–47.

    Article  CAS  PubMed  Google Scholar 

  53. Hamdy RC, Murnane B, Perera N, Woodcock K, Koch IM. The pharmacokinetics of benoxaprofen in elderly subjects. Eur J Rheumatol Inflamm 1982;52:69–75.

    Google Scholar 

  54. Boelsterli UA. Editorial. Curr Drug Metab.2011;12:213–4.

    CAS  PubMed  Google Scholar 

  55. Teschke R, Uetrecht J. Mechanisms of idiosyncratic drug induced liver injury (DILI): unresolved basis issues. Ann Transl Med. 2021;9:730–46. https://doi.org/10.21037/atm-2020-ubih-05.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Daly AK, Aithal GP, Leathart JBS, Swansbury RA, Dang TS, Day CP. Genetic susceptibility to diclofenac-induced hepatptoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterol. 2007;132:272–81. https://doi.org/10.1053/J.gastro.2006.11.023.

    Article  CAS  Google Scholar 

  57. FDA. Safety testing of drug metabolites. Guidance for industry. Revision 2. 2020. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.

  58. ICH. Guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. M2(R2). 2009. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-m3r2-non-clinical-safety-studies-conduct-human-clinical-trials-marketing-authorisation_en.pdf.

  59. Walles M, Brown AP, Zimmerlin A, End P. New perspectives on drug-induced liver injury risk assessment of acyl glucuronides. Chem Res Toxicol. 2020;33:1551–60. https://doi.org/10.1021/acs.chemrestox.0c00131.

    Article  CAS  PubMed  Google Scholar 

  60. Patel SF. Bioanalytical challenges and strategies for accurately measuring acyl glucuronide metabolites in biological fluids. Biomed Chromatogr. 2019;34:e4640 https://doi.org/10.1002/bmc.4640.

    Article  PubMed  Google Scholar 

  61. Yuan L, Xu XS, Ji QC. Challenges and recommendations in developing LC-MS/MS bioanalytical assays of labile glucuronides and parent compounds in the presence of glucuronide metabolites. Bioanalysis 2020;12:615–24.

    Article  CAS  PubMed  Google Scholar 

  62. Prueksaritanont T, Lin JH, Baillie TA. Complicating factors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites. Toxicol Appl Pharm. 2006;217:143–52. https://doi.org/10.1016/j.taap.2006.08.009.

    Article  CAS  Google Scholar 

  63. Zhang D, Raghavan N, Wang L, Xue Y, Obermeier M, Chen S, Tao S, Zhang H, Cheng PT, Li W, Ramanathan R, Yang Z, Humphreys WG. Plasma stability-dependent circulation of acyl glucuronide metabolites in humans: how circulating metabolite profiles of muraglitazar and peliglitazar can lead to misleading risk assessment. Drug Metab Dispos. 2011;39:123–31. https://doi.org/10.1124/dmd.110.035048.

    Article  PubMed  Google Scholar 

  64. Smith DA, Hammond T, Baillie TA. Safety assessment of acyl glucuronides – a simplified paradigm. Drug Metab Dispos. 2018;46:908–12. https://doi.org/10.1124/dmd.118.080515.

    Article  CAS  PubMed  Google Scholar 

  65. Baillie TA, Cayen MN, Fouda H, Gerson RJ, Green JD, Grossman SJ, Klunk LJ, LeBlanc B, Perkins DG, Shipley LA. Drug metabolites in safety testing. Toxicol Appl Pharm. 2002;182:188–96. https://doi.org/10.1006/taap.2002.9440.

    Article  CAS  Google Scholar 

  66. Van Vleet TR, Liu H, Lee A, Blomme EAG. Acyl glucuronide metabolites: implications for drug safety assessment. Toxicol Lett. 2017;272:1–7. https://doi.org/10.1016/j.toxlet.2017.03.003.

    Article  PubMed  Google Scholar 

  67. Lassila T, Hokkanen J, Aatsinki S-M, Mattila S, Turpeinen M, Tolonen A. Toxicity of carboxylic acid-containing drugs: the role of acyl migration and CoA conjugation investigated. Chem Res Toxicol. 2015;28:2292–303. https://doi.org/10.1021/acs.chemrestox.5b00315.

    Article  CAS  PubMed  Google Scholar 

  68. Yu ZJ, Le H, Tang J, Yue Q, Zhang J, Murray B, Liu X, Smith BJ, Subramanian R. 18O-Enabled high-throughput acyl glucuronide stability assay. Chem Res Toxicol. 2022;35:1400–9. https://doi.org/10.1021/acs.chemrestox.2c00156.

    Article  CAS  PubMed  Google Scholar 

  69. Harada H, Toyoda Y, Abe Y, Endo T, Takeda H. Quantitative evaluation of reactivity and toxicity of acyl glucuronides by [35S]cysteine trapping. Chem Res Toxicol. 2019;32:1955–64. https://doi.org/10.1021/acs.chemrestox.9b00111.

    Article  CAS  PubMed  Google Scholar 

  70. Iwamura A, Ito M, Mitsui H, Hasegawa J, Kosaka K, Kino I, Tsuda M, Nakajima M, Yokoi T, Kume T. Toxicological evaluation of acyl glucuronides utilizing half-lives, peptide adducts, and immunostimulation assays. Toxicol Vitr. 2015;30:241–9. https://doi.org/10.1016/j.tiv.2015.10.013.

    Article  CAS  Google Scholar 

  71. Shibazaki C, Mashita O, Takahashi K, Nakamura S, Mashino T, Ohe T. Development of a fluorescent-labeled trapping reagent to detect reactive acyl glucuronides. Chem Res Toxicol. 2021;34:2343–52. https://doi.org/10.1021/acs.chemrestox.1c00236.

    Article  CAS  PubMed  Google Scholar 

  72. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol. 2004;17:3–16. https://doi.org/10.1021/tx034170b.

    Article  CAS  PubMed  Google Scholar 

  73. Iwamura A, Nakajima M, Oda S, Yokoi T. Toxicological potential of acyl glucuronides and its assessment. Drug Metab Pharmacokinet. 2017;32:2–11. https://doi.org/10.1016/j.dmpk.2016.11.002.

    Article  CAS  PubMed  Google Scholar 

  74. Vaz ADN, Wang WW, Bessire AJ, Sharma R, Hagen AE. A rapid and specific derivatization procedure to identify acyl-glucuronides by mass spectrometry. Rapid Commun Mass Spectrom. 2010;24:2109–21. https://doi.org/10.1002/rcm.4621.

    Article  CAS  PubMed  Google Scholar 

  75. Niyonsaba E, Easton MW, Feng E, Yu Z, Zhang Z, Sheng H, Kong J, Easterling LF, Milton J, Chobanian, Deprez NR, Cancilla MT, Kilaz G, Kenttämaa HI. Differentiation of deprotonated acyl-, N-, and O-glucuronide drug metabolites by using tandem mass spectrometry based on gas-phase ion-molecule reactions followed by collision-activated dissociation. Anal Chem. 2019;91:11388–96. https://doi.org/10.1021/acs.analchem.9b02717.

    Article  CAS  PubMed  Google Scholar 

  76. Guo Y, Shah A, Oh E, Chowdhury SK, Zhu X. Determination of acyl-, O-, and N-glucuronide using chemical derivatization coupled with liquid chromatography-high-resolution mass spectrometry. Drug Metab Dispos. 2022;50:716–24. https://doi.org/10.1124/dmd.122.000832.

    Article  CAS  PubMed  Google Scholar 

  77. Higton D, Palmer ME, Vissers JPC, Mullin LG, Plumb RS, Wilson ID. Use of cyclic ion mobility spectrometry (cIM)-mass spectrometry to study the intramolecular transacylation of diclofenac acyl glucuronide. Anal Chem. 2021;93:7413–21. https://doi.org/10.1021/acs.analchem.0c04487.

    Article  CAS  PubMed  Google Scholar 

  78. Tailor A, Waddington JC, Meng X, Park BK. Mass spectrometric and functional aspects of drug-protein conjugation. Chem Res Toxicol. 2016;29:1912–35. https://doi.org/10.1021/acs.chemrestox.6b00147.

    Article  CAS  PubMed  Google Scholar 

  79. Walker GS, Atherton J, Bauman J, Kohl C, Lam W, Reily M, Lou Z, Mutlib A. Determination of degradation pathways and kinetics of acyl glucuronides by NMR spectroscopy. Chem Res Toxicol. 2007;20:876–86. https://doi.org/10.1021/tx600297u.

    Article  CAS  PubMed  Google Scholar 

  80. Buevich AV, He CQ, Pio B, Samuel K, Mitra K, Sherer EC, Cancilla MT, Chobanian HR. Driving to a better understanding of acyl glucuronide transformations using NMR and molecular modeling. Chem Res Toxicol. 2022;35:459–74. https://doi.org/10.1021/acs.chemrestox.1c00366.

    Article  CAS  PubMed  Google Scholar 

  81. Rennie GR, Barden TC, Bernier SG, Carvalho A, Deming R, Germano P, Hudson C, Im G-YJ, Iyengar RR, Jia L, Jung J, Kim E, Lee TW-H, Mermerian A, Moore J, Nakai T, Perl NR, Tobin J, Zimmer DP, Renhowe PA. Bioorg Med Chem Lett. 2021;40:127886 https://doi.org/10.1016/j.bmcl.2021.127886.

    Article  CAS  PubMed  Google Scholar 

  82. Ballatore C, Huryn DM, Smith AB. Carboxylic acid (bio)isosteres in drug design. ChemMedChem 2013;8:385–95. https://doi.org/10.1002/cmdc.201200585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Laine L, Goldkind L, Curtis SP, Connors LG, Yanqiong Z, Cannon CP. How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial. Am J Gastroenterol. 2009;104:356–62. https://doi.org/10.1038/ajg.2008.149.

    Article  PubMed  Google Scholar 

  84. Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol Drug Saf. 2006;15:213–20. https://doi.org/10.1002/pds.1207.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, 98195-7610, USA

    Thomas A. Baillie

Authors
  1. Thomas A. Baillie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas A. Baillie.

Ethics declarations

Conflict of interest

The author declares no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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

Baillie, T.A. Acyl glucuronides–mediators of drug-induced toxicities?. Med Chem Res 32, 1249–1262 (2023). https://doi.org/10.1007/s00044-023-03062-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-023-03062-6

Keywords

Search

Navigation