TOXICOLOGY: Present-Day Difficulties for Investigating Safety Science and Target Safety Evaluation of Major Human Hepatocytes

Year : 2024 | Volume : 14 | Issue : 03 | Page : 31 40
    By

    Manisha Agrahari,

  • Raj Kamal Sharma,

  1. Assistant Professor, Department of Morphology, St.Stephene’s College of Nursing Supaul, Bihar, India
  2. Associate Professor, Department of Morphology, Karaganda Medical University, , Kazakhstan

Abstract

Preclinical toxicology has developed into a more thorough understanding of toxicity pathways from its descriptive beginnings. Technological developments have made it possible to forecast safety occurrences, mitigate adverse effects, and create safety biomarkers. Because they are able to self-renew and specialize into different types of human body cells, stem cells are currently being employed for in vitro toxicological applications. However, as compared to primary human hepatocytes, stem cell-derived HLCs perform worse in the liver. More research on the concentration-and/or time-response of rifampin, phenytoin, clotrimazole, and phenobarbital in six formulations were carried out. By using Western blotting, bupropion hydroxylation, and testosterone 6β-hydroxylation, respectively, CYP2B6 and CYP3A4 protein and activity were evaluated. Huh7 cells cotransfected with CYP2B6 (NR1)5-LUC reporter plasmid and hPXR were used in reporter gene experiments to assess hPXR activation by the 14 drugs. The LUC reporter  Transcripts of nuclear receptors (aryl hydrocarbon receptor, pregnane X receptor, constitutive androstane receptor, peroxisome proliferator-activated receptor α), P450s (CYP1A2, 2C9, 2D6, 2E1, 3A4), phase 2 enzymes (UGT1A1, GSTA1, GSTA4, GSTM1), and other liver-specific functions were found to be expressed at comparable levels in both confluent differentiated and The levels of numerous transcripts were significantly raised in the presence of 2% dimethyl sulfoxide. Measurement of baseline activity of many P450s and their response to prototypical inducers, as well as study of metabolic profiles and cytotoxicity of several drugs, verified the functional similarity of HepaRG cells to primary cultured human hepatocytes.

Keywords: drug safety, risk assessment, signal transduction, HepaRG, peroxisome proliferator-activated receptor α, , pregnane X receptor

[This article belongs to Research and Reviews: A Journal of Toxicology ]

How to cite this article:
Manisha Agrahari, Raj Kamal Sharma. TOXICOLOGY: Present-Day Difficulties for Investigating Safety Science and Target Safety Evaluation of Major Human Hepatocytes. Research and Reviews: A Journal of Toxicology. 2024; 14(03):31-40.
How to cite this URL:
Manisha Agrahari, Raj Kamal Sharma. TOXICOLOGY: Present-Day Difficulties for Investigating Safety Science and Target Safety Evaluation of Major Human Hepatocytes. Research and Reviews: A Journal of Toxicology. 2024; 14(03):31-40. Available from: https://journals.stmjournals.com/rrjot/article=2024/view=190427


References

  1. Gerets HHJ, Tilmant K, Gerin B, Chanteux H, Depelchin BO, Dhalluin S, et al. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol Toxicol. 2012;28(2):69–87. https://doi.org/10.1007/s10565-011-9208-4
  2. Hood L. Systems Biology and P4 Medicine: Past, Present, and Future. Rambam Maimonides Med J. 2013;4(2) https://doi.org/10.5041/rmmj.10112
  3. Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian J Chem. 2019;12(7):908–31. https://doi.org/10.1016/j.arabjc.2017.05.011
  4. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of Aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327–60. https://doi.org/10.1086/525258
  5. Cuervas-Mons V, Martinez AJ, Dekker A, Starzl TE, Van Thiel DH. Adult liver transplantation: An analysis of the early causes of death in 40 consecutive cases. Hepatology. 1986;6(3):495–501. https://doi.org/10.1002/hep.1840060329
  6. Sharma P, Sethi RS. In Vivo Exposure of Deltamethrin Dysregulates the NFAT Signalling Pathway and Induces Lung Damage. J Toxicol. 2024;2024(1). https://doi.org/10.1155/2024/5261994
  7. Dambach DM, Andrews BA, Moulin F. New Technologies and Screening Strategies for Hepatotoxicity: Use of In Vitro Models. Toxicol Pathol. 2005;33(1):17–26. https://doi.org/10.1080/01926230590522284
  8. Sessa C, Vigano L, Grasselli G, Trigo J, Marimon I, Llado A, et al. Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing. Eur J Cancer. 2006;42(1):171–8.
  9. Shou M, Hayashi M, Pan Y, Xu Y, Morrissey K, Xu L, et al. Modeling, prediction, and in vitro in vivo correlation of CYP3A4 induction. Drug Metab Dispos. 2008;36(12):2355–70.
  10. Changing the Face of Modern Medicine: Stem Cell and Gene Therapy Organized Jointly by the European Society of Gene & Cell Therapy (ESGCT), International Society for Stem Cell Research (ISSCR) and the French Society of Gene and Cell Therapy (SFTCG) Lausanne, Switzerland October 16–19, 2018 Abstracts. Hum Gene Ther. 2018;29(12)–A169. https://doi.org/10.1089/hum.2018.29077.abstracts
  11. Smith DA. Induction and drug development. Eur J Pharm Sci. 2000;11(2):185–9.
  12. Smith DA, Obach RS. Metabolites in safety testing (MIST): Considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chem Res Toxicol. 2009;22(2):267–79.
  13. Soars MG, Petullo DM, Eckstein JA, Kasper SC, Wrighton SA. An assessment of UDP-glucuronosyltransferase induction using primary human hepatocytes. Drug Metab Dispos. 2004;32(2):140–8.
  14. Spaldin V, Madden S, Adams DA, Edwards RJ, Davies DS, Park BK. Determination of human hepatic cytochrome P4501A2 activity in vitro using tacrine as an isoenzyme-specific probe. Drug Metab Dispos. 1995;23(8):929–34.
  15. Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, et al. Drug-Induced Liver Injury Network (DILIN) Prospective Study. Drug Saf. 2009;32(1):55–68. https://doi.org/10.2165/00002018-200932010-00005
  16. Kirstein SL, Atienza JM, Xi B, Zhu J, Yu N, Wang X, et al. Live Cell Quality Control and Utility of Real-Time Cell Electronic Sensing for Assay Development. Assay Drug Dev Technol. 2006;4(5):545–53. https://doi.org/10.1089/adt.2006.4.545
  17. Xia M, Huang R, Witt KL, Southall N, Fostel J, Cho M, et al. Compound Cytotoxicity Profiling Using Quantitative High-Throughput Screening. Environ Health Perspect. 2007;116(3):284–91. https://doi.org/10.1289/ehp.10727
  18. Vistejnova L, Dvorakova J, Hasova M, Muthny T, Velebny V, Soucek K, et al. The comparison of impedance-based method of cell proliferation monitoring with commonly used metabolic-based techniques. PubMed. 2009;30(Suppl 1):121–7. https://pubmed.ncbi.nlm.nih.gov/20027157
  19. Anderson L, Hunter CL. Quantitative Mass Spectrometric Multiple Reaction Monitoring Assays for Major Plasma Proteins. Mol Cell Proteomics. 2005;5(4):573–88. https://doi.org/10.1074/mcp.m500331-mcp200
Regular Issue Subscription Review Article
Volume 14
Issue 03
Received 03/10/2024
Accepted 24/10/2024
Published 19/11/2024
Publication Time 47 Days
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