Role of Carboxylesterases in Xenobiotic Metabolism and Detoxification: Insights for Cheminformatics Approaches

Year : 2024 | Volume : 02 | Issue : 02 | Page : 9 17
    By

    Sakshi Chaudhary,

  • Neetu Saharan,

  1. Assistant Professor, Department of Biotechnology, Dr. K.N. Modi Institute of Pharmaceutical Education and Research, Modinagar, Ghaziabad, Uttar Pradesh, India
  2. Assistant Professor, Department of Biotechnology, Dr. K.N. Modi Institute of Pharmaceutical Education and Research, Modinagar, Ghaziabad, Uttar Pradesh, India

Abstract

Xenobiotics, which include a wide range of environmental pollutants, food additives, drugs, and carcinogens, are foreign chemical entities that enter the human body and may accumulate, leading to toxic effects. Phase I and phase II metabolic responses are among the detoxification procedures that are necessary to lessen these negative consequences. This review highlights the pivotal role of carboxylesterases (CES), enzymes involved in the hydrolysis of ester, amide, and thioester bonds in xenobiotics, in the metabolism and detoxification of these substances. We discuss the structural and functional properties of CES, their tissue distribution, and the implications of their activity in drug metabolism and environmental toxin clearance. In the context of cheminformatics, we explore how computational models can assist in predicting CES activity, understanding substrate specificity, and designing drug molecules or inhibitors that modulate CES activity. The information presented here provides valuable insights for both pharmacological applications and environmental health assessments.

Keywords: Carboxylesterases, Xenobiotics, Detoxification, Phase I and II Metabolism, Cheminformatics, Drug Metabolism, Enzyme Modulation

[This article belongs to International Journal of Cheminformatics ]

How to cite this article:
Sakshi Chaudhary, Neetu Saharan. Role of Carboxylesterases in Xenobiotic Metabolism and Detoxification: Insights for Cheminformatics Approaches. International Journal of Cheminformatics. 2025; 02(02):9-17.
How to cite this URL:
Sakshi Chaudhary, Neetu Saharan. Role of Carboxylesterases in Xenobiotic Metabolism and Detoxification: Insights for Cheminformatics Approaches. International Journal of Cheminformatics. 2025; 02(02):9-17. Available from: https://journals.stmjournals.com/ijci/article=2025/view=202226


References

  1. Joseph, P. (2017). Transcriptomics in toxicology. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 109(Pt 1), 650–662. doi:10.1016/j.fct.2017.07.031
  2. Mansuy, D. (2013). Le métabolisme des xénobiotiques : effets bénéfiques, effets néfastes. Biologie aujourd’hui, 207(1), 33– doi:10.1051/jbio/2013003
  3. Patterson, A. D., Gonzalez, F. J., & Idle, J. R. (2010). Xenobiotic metabolism: a view through the metabolometer. Chemical Research in Toxicology, 23(5), 851– doi:10.1021/tx100020p
  4. Detoxification and Substance Abuse Treatment Treatment Improvement Protocol (TIP) Series. (2006). Rockville (MD).
  5. Kreitinger, J. M., Beamer, C. A., & Shepherd, D. M. (2016). Environmental immunology: Lessons learned from exposure to a select panel of immunotoxicants. The Journal of Immunology, 196(8), 3217–3225. doi:10.4049/jimmunol.1502149
  6. Croom, E. (2012). Metabolism of xenobiotics of human environments. Progress in Molecular Biology and Translational Science, 112, 31–88. doi:10.1016/B978-0-12-415813-9.00003-9
  7. Godin, S. J., Scollon, E. J., Hughes, M. F., Potter, P. M., DeVito, M. J., & Ross, M. K. (2006). Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: differential oxidative and hydrolytic metabolism by humans and rats. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 34(10), 1764–1771. doi:10.1124/dmd.106.010058
  8. The Role of Carboxylesterases in Therapeutic Intervention of Nerve Gases Poisoning Sigrun Hanne Sterri, Frode Fonnum, in Handbook of Toxicology of Chemical Warfare Agents. (2015).
  9. Yan, B. (2014). Carboxylesterases. In Encyclopedia of Toxicology (pp. 695–698). Elsevier.
  10. Bachmann, K. (2009). Drug Metabolism. In Pharmacology (pp. 131–173). Elsevier.
  11. Koppel, N., Maini Rekdal, V., & Balskus, E. P. (2017). Chemical transformation of xenobiotics by the human gut microbiota. Science (New York, N.Y.), 356(6344). doi:10.1126/science.aag2770
  12. Abdelsalam, N. A., Ramadan, A. T., ElRakaiby, M. T., & Aziz, R. K. (2020). Toxicomicrobiomics: The human microbiome vs. Pharmaceutical, dietary, and environmental xenobiotics. Frontiers in Pharmacology, 11, 390. doi:10.3389/fphar.2020.00390
  13. Clarke, G., Sandhu, K. V., Griffin, B. T., Dinan, T. G., Cryan, J. F., Hyland, N. P. (2019). Gut reactions: breaking down xenobiotic-microbiome interactions. Pharmacol. Rev. 71, 198–224. doi: 10.1124/pr.118.015768
  14. Wang, D., Zou, L., Jin, Q., Hou, J., Ge, G., & Yang, L. (2018). Human carboxylesterases: a comprehensive review. Acta Pharmaceutica Sinica. B, 8(5), 699–712. doi:10.1016/j.apsb.2018.05.005
  15. Hatfield, M. J., Umans, R. A., Hyatt, J. L., Edwards, C. C., Wierdl, M., Tsurkan, L., … Potter, P. M. (2016). Carboxylesterases: General detoxifying enzymes. Chemico-Biological Interactions, 259(Pt B), 327–331. doi:10.1016/j.cbi.2016.02.011
  16. Sanghani S.P., Sanghani P.C., Schiel M.A., Bosron W.F. Human carboxylesterases: an update on CES1, CES2 and CES3. Protein Pept Lett. 2009;16:1207– doi: 10.2174/092986609789071324.
  17. Satoh T., Hosokawa M. Structure, function and regulation of carboxylesterases. Chem Biol Interact. 2006;162:195–211. doi: 10.1016/j.cbi.2006.07.001.
  18. Satoh T., Hosokawa M. The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol. 1998;38:257–288. doi: 10.1146/annurev.pharmtox.38.1.257.
  19. Ross M.K., Crow J.A. Human carboxylesterases and their role in xenobiotic and endobiotic metabolism. J Biochem Mol Toxicol. 2007;21:187–196. doi: 10.1002/jbt.20178.
  20. Hosokawa M. Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs. Molecules. 2008;13:412–431. doi: 10.3390/molecules13020412.
  21. Imai T. Human carboxylesterase isozymes: catalytic properties and rational drug design. Drug Metab Pharmacokinet. 2006;21:173– doi: 10.2133/dmpk.21.173.
  22. Redinbo M.R., Potter P.M. Mammalian carboxylesterases: from drug targets to protein therapeutics. Drug Discov Today. 2005;10:313–325. doi: 10.1016/S1359-6446(05)03383-0.
  23. Satoh T., Taylor P., Bosron W.F., Sanghani S.P., Hosokawa M., La Du. B.N. Current progress on esterases: from molecular structure to function. Drug Metab Dispos. 2002;30:488–493. doi: 10.1124/dmd.30.5.488.
  24. Potter P.M., Wolverton J.S., Morton C.L., Wierdl M., Danks M.K. Cellular localization domains of a rabbit and a human carboxylesterase: influence on irinotecan (CPT-11) metabolism by the rabbit enzyme. Cancer Res. 1998;58:3627–3632.
  25. Zhu H.J., Wang X., Gawronski B.E., Brinda B.J., Angiolillo D.J., Markowitz J.S. Carboxylesterase 1 as a determinant of clopidogrel metabolism and activation. J Pharmacol Exp Ther. 2013;344:665–672. doi: 10.1124/jpet.112.201640.
  26. Zhu H.J., Markowitz J.S. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos. 2009;37:264–267. doi: 10.1124/dmd.108.024943.
  27. Nishi K., Huang H., Kamita S.G., Kim I.H., Morisseau C., Hammock B.D. Characterization of pyrethroid hydrolysis by the human liver carboxylesterases CES-1 and CES-2. Arch Biochem Biophys. 2006;445:115–123. doi: 10.1016/j.abb.2005.11.005.
  28. Imai T., Ohura K. The role of intestinal carboxylesterase in the oral absorption of prodrugs. Curr Drug Metab. 2010;11:793–805. doi: 10.2174/138920010794328904.
  29. Lian J., Nelson R., Lehner R. Carboxylesterases in lipid metabolism: from mouse to human. Protein Cell. 2018;9:178– doi: 10.1007/s13238-017-0437-z.
  30. Alam M., Ho S., Vance D.E., Lehner R. Heterologous expression, purification, and characterization of human triacylglycerol hydrolase. Protein Expr Purif. 2002;24:33– doi: 10.1006/prep.2001.1553.
  31. Ruby M.A., Massart J., Hunerdosse D.M., Schönke M., Correia J.C., Louie S.M. Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance. Cell Rep. 2017;18:636–646. doi: 10.1016/j.celrep.2016.12.070.
  32. Crow J.A., Herring K.L., Xie S., Borazjani A., Potter P.M., Ross M.K. Inhibition of carboxylesterase activity of THP1 monocytes/macrophages and recombinant human carboxylesterase 1 by oxysterols and fatty acids. Biochim Biophys Acta. 2010;1801:31–41. doi: 10.1016/j.bbalip.2009.09.002.
  33. Alam M., Vance D.E., Lehner R. Structure-function analysis of human triacylglycerol hydrolase by site-directed mutagenesis: identification of the catalytic triad and a glycosylation site. Biochemistry. 2002;41:6679–6687. doi: 10.1021/bi0255625
  34. Wang D.D., Zou L.W., Jin Q., Hou J., Ge G.B., Yang L. Recent progress in the discovery of natural inhibitors against human carboxylesterases. Fitoterapia. 2017;117:84–95. doi: 10.1016/j.fitote.2017.01.010.
  35. Dominguez E., Galmozzi A., Chang J.W., Hsu K.L., Pawlak J., Li W. integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes. Nat Chem Biol. 2014;10:113–121. doi: 10.1038/nchembio.1429.
  36. Crow J.A., Middleton B.L., Borazjani A., Hatfield M.J., Potter P.M., Ross M.K. Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages. Biochim Biophys Acta. 2008;1781:643–654. doi: 10.1016/j.bbalip.2008.07.005.
  37. Yoon K.J.P., Hyatt J.L., Morton C.L., Lee R.E., Potter P.M., Danks M.K. Characterization of inhibitors of specific carboxylesterases: development of carboxylesterase inhibitors for translational application. Mol Cancer Ther. 2004;3:903–909.
  38. Xu Y., Zhang C., He W., Liu D. Regulations of xenobiotics and endobiotics on carboxylesterases: a comprehensive review. Eur J Drug Metab Pharmacokinet. 2016;41:321– doi: 10.1007/s13318-016-0326-5.
  39. Hicks L.D., Hyatt J.L., Stoddard S., Tsurkan L., Edwards C.C., Wadkins R.M. Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan; CPT-11) toxicity. J Med Chem. 2009;52:3742–3752. doi: 10.1021/jm9001296.
  40. Aranda, J., Cerqueira, N. M. F. S. A., Fernandes, P. A., Roca, M., Tuñon, I., & Ramos, M. J. (2014). The catalytic mechanism of carboxylesterases: a computational study. Biochemistry, 53(36), 5820– doi:10.1021/bi500934j
  41. Liebler, D. C., & Guengerich, F. P. (2005). Elucidating mechanisms of drug-induced toxicity. Nature Reviews. Drug Discovery, 4(5), 410– doi:10.1038/nrd1720
  42. Chambers, J. P., Hartgraves, S. L., Murphy, M. R., Wayner, M. J., Kumar, N., & Valdes, J. J. (1991). Effects of three reputed carboxylesterase inhibitors upon rat serum esterase activity. Neuroscience and Biobehavioral Reviews, 15(1), 85–88. doi:10.1016/s0149-7634(05)80096-x
  43. Cashman, J. R., Perotti, B. Y., Berkman, C. E., & Lin, J. (1996). Pharmacokinetics and molecular detoxication. Environmental Health Perspectives, 104 Suppl 1, 23–40. doi:10.1289/ehp.96104s123
  44. Jones, R. D., Taylor, A. M., Tong, E. Y., & Repa, J. J. (2013). Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 41(1), 40–49. doi:10.1124/dmd.112.048397
  45. Ross, M. K., & Crow, J. A. (2007). Human carboxylesterases and their role in xenobiotic and endobiotic metabolism. Journal of Biochemical and Molecular Toxicology, 21(4), 187–196. doi:10.1002/jbt.20178
  46. Tsujita, T., & Okuda, H. (1994). The synthesis of fatty acid ethyl ester by carboxylester lipase. European Journal of Biochemistry, 224(1), 57–62. doi:10.1111/j.1432-1033.1994.tb19994.x
  47. Shibata, Y., Takahashi, H., Chiba, M., & Ishii, Y. (2002). Prediction of hepatic clearance and availability by cryopreserved human hepatocytes: an application of serum incubation method. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 30(8), 892–896. doi:10.1124/dmd.30.8.892
  48. Hodgson, E., & Levi, P. E. (1996). Pesticides: an important but underused model for the environmental health sciences. Environmental Health Perspectives, 104 Suppl 1, 97–106. doi:10.1289/ehp.96104s197
  49. Spitzen, J., Koelewijn, T., Mukabana, W. R., & Takken, W. (2017). Effect of insecticide-treated bed nets on house-entry by malaria mosquitoes: The flight response recorded in a semi-field study in Kenya. Acta Tropica, 172, 180– doi:10.1016/j.actatropica.2017.05.008
  50. Clark, N. W., Scott, R. C., Blain, P. G., & Williams, F. M. (1993). Fate of fluazifop butyl in rat and human skin in vitro. Archives of Toxicology, 67(1), 44– doi:10.1007/bf02072034
  51. Cantalamessa, F. (1993). Acute toxicity of two pyrethroids, permethrin, and cypermethrin in neonatal and adult rats. Archives of Toxicology, 67(7), 510– doi:10.1007/bf01969923
  52. Casida, J. E., Ueda, K., Gaughan, L. C., Jao, L. T., & Soderlund, D. M. (1975). Structure-biodegradability relationships in pyrethroid insecticides. Archives of Environmental Contamination and Toxicology, 3(4), 491– doi:10.1007/bf02220819
  53. Brzezinski, M. R., Abraham, T. L., Stone, C. L., Dean, R. A., & Bosron, W. F. (1994). Purification and characterization of a human liver cocaine carboxylesterase that catalyzes the production of benzoylecgonine and the formation of cocaethylene from alcohol and cocaine. Biochemical Pharmacology, 48(9), 1747–1755. doi:10.1016/0006-2952(94)90461-8
  54. Durrer, A., Walther, B., Racciatti, A., Boss, G., & Testa, B. (1991). Structure-metabolism relationships in the hydrolysis of nicotinate esters by rat liver and brain subcellular fractions. Pharmaceutical Research, 8(7), 832–839. doi:10.1023/a:1015839109449
  55. Inoue, M., Morikawa, M., Tsuboi, M., Ito, Y., & Sugiura, M. (1980). Comparative study of human intestinal and hepatic esterases as related to enzymatic properties and hydrolizing activity for ester-type drugs. The Japanese Journal of Pharmacology, 30(4), 529–535. doi:10.1254/jjp.30.529
  56. Luttrell, W. E., & Castle, M. C. (1988). Species differnces in the hydrolysis of meperdine and its inhibition by organophosphate compounds. Toxicological Sciences: An Official Journal of the Society of Toxicology, 11(1), 323– doi:10.1093/toxsci/11.1.323
  57. Stott, W. T., & McKenna, M. J. (1985). Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fundamental and Applied Toxicology: Official Journal of the Society of Toxicology, 5(2), 399–404. doi:10.1016/0272-0590(85)90088-0
  58. Potter, P. M., & Wadkins, R. M. (2006). Carboxylesterases–detoxifying enzymes and targets for drug therapy. Current Medicinal Chemistry, 13(9), 1045– doi:10.2174/092986706776360969
  59. Wikipedia contributors. (2024, July 7). Drug metabolism. Retrieved from Wikipedia, The Free Encyclopedia website: https://en.wikipedia.org/w/index.php?title=Drug_metabolism&oldid=1233160811
Regular Issue Subscription Review Article
Volume 02
Issue 02
Received 24/12/2024
Accepted 25/01/2025
Published 18/02/2025
Publication Time 56 Days
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