Mechanistic, Functional, and Clinical Aspects of Pro-inflammatory Cytokine Mediated Regulation of ADME Gene Expression in 3D Human Liver Spheroids.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
22
12
2022
accepted:
05
06
2023
medline:
21
8
2023
pubmed:
12
6
2023
entrez:
12
6
2023
Statut:
ppublish
Résumé
During systemic inflammation, pro-inflammatory cytokines alter metabolism and transport of drugs affecting the clinical outcome. We used an in vivo like human 3D liver spheroid model to study the effects and mechanisms of pro-inflammatory cytokines on the expression of 9 different genes encoding enzymes responsible for the metabolism of > 90% of clinically used drugs. Treatment of spheroids with pathophysiologically relevant concentrations of IL-1β, IL-6, or TNFα resulted in a pronounced decrease in mRNA expression of CYP3A4 and UGT2B10 within 5 hours. The reduction of CYP1A2, CYP2C9, CYP2C19, and CYP2D6 mRNA expression was less pronounced, whereas the pro-inflammatory cytokines caused increased CYP2E1, and UGT1A3 mRNA expression. The cytokines did not influence expression of key nuclear proteins, nor the activities of specific kinases involved in the regulation of genes encoding drug metabolizing enzymes. However, ruxolitinib, a JAK1/2 inhibitor, inhibited the IL-6 dependent increase in CYP2E1 and the decrease in CYP3A4 and UGT2B10 mRNA expression. We evaluated the effect of TNFα in hepatocytes in 2D plates and found a rapid decrease in drug-metabolizing enzyme mRNA both in the absence or presence of the cytokines. Taken together, these data suggest that pro-inflammatory cytokines regulate multiple gene- and cytokine-specific events seen in in vivo and in 3D but not in 2D liver models. We propose that the 3D spheroid system is suitable for the prediction of drug metabolism under conditions of inflammation and constitutes a versatile system for short- and long-term preclinical and mechanistic studies of cytokine-induced changes in drug metabolism.
Substances chimiques
Cytochrome P-450 CYP2E1
EC 1.14.13.-
Cytochrome P-450 Enzyme System
9035-51-2
Cytokines
0
Tumor Necrosis Factor-alpha
0
Cytochrome P-450 CYP3A
EC 1.14.14.1
Interleukin-6
0
RNA, Messenger
0
UGT2B10 protein, human
EC 2.4.1.-
Glucuronosyltransferase
EC 2.4.1.17
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
673-685Informations de copyright
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Références
Lenoir, C., Rollason, V., Desmeules, J.A. & Samer, C.F. Influence of inflammation on cytochromes P450 activity in adults: a systematic review of the literature. Front. Pharmacol. 12, 733935 (2021).
Duthaler, U. et al. Liver cirrhosis affects the pharmacokinetics of the six substrates of the Basel phenotyping cocktail differently. Clin. Pharmacokinet. 61, 1039-1055 (2022).
Frye, R.F. et al. Liver disease selectively modulates cytochrome P450-mediated metabolism. Clin. Pharmacol. Ther. 80, 235-245 (2006).
Dunvald, A.D., Järvinen, E., Mortensen, C. & Stage, T.B. Clinical and molecular perspectives on inflammation-mediated regulation of drug metabolism and transport. Clin. Pharmacol. Ther. 112, 277-290 (2022).
Bell, C.C. et al. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci. Rep. 6, 25187 (2016).
Vorrink, S.U. et al. Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. FASEB J. 6, 2696-2708 (2017).
Kim, H., Kim, H.-S., Youn, J.-C., Shin, E.-C. & Park, S. Serum cytokine profiles in healthy young and elderly population assessed using multiplex bead-based immunoassays. J. Transl. Med. 9, 113 (2011).
Lyke, K.E. et al. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect. Immun. 72, 5630-5637 (2004).
Mayo, P.R., Skeith, K., Russell, A.S. & Jamali, F. Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis. Br. J. Clin. Pharmacol. 50, 605-613 (2000).
Inam Illahi, M., Amjad, S., Alam, S.M., Ahmed, S.T., Fatima, M. & Shahid, M.A. Serum tumor necrosis factor-alpha as a competent biomarker for evaluation of disease activity in early rheumatoid arthritis. Cureus. 13, e15314 (2021).
Jahid, M., Rehan-Ul-Haq, C.D., Avasthi, R. & Ahmed, R.S. Association of polymorphic variants in IL1B gene with secretion of IL-1β protein and inflammatory markers in north Indian rheumatoid arthritis patients. Gene 641, 63-67 (2018).
Szekanecz, Z., Strieter, R.M., Kunkel, S.L. & Koch, A.E. Chemokines in rheumatoid arthritis. Springer Semin. Immunopathol. 20, 115-132 (1998).
Chen, L.Y.C., Hoiland, R.L., Stukas, S., Wellington, C.L. & Sekhon, M.S. Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome. Eur. Respir. J. 56, 2003006 (2020).
Chen, X. et al. Consecutive monitoring of interleukin-6 is needed for COVID-19 patients. Virol. Sin. 36, 1093-1096 (2021).
Angulo, J. et al. Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes virus. PLoS Negl. Trop. Dis. 11, e0005757 (2017).
Hurrell, T. et al. Human liver spheroids as a model to study aetiology and treatment of hepatic fibrosis. Cell 9, 964 (2020).
Febvre-James, M., Bruyère, A., Le Vée, M. & Fardel, O. The JAK1/2 inhibitor Ruxolitinib reverses Interleukin-6-mediated suppression of drug-detoxifying proteins in cultured human hepatocytes. Drug Metab. Dispos. 46, 131-140 (2018).
Hendriks, D.F.G. et al. Clinically relevant cytochrome P450 3A4 induction mechanisms and drug screening in three-dimensional spheroid cultures of primary human hepatocytes. Clin. Pharmacol. Ther. 108, 844-855 (2020).
Heinrich, P.C., Behrmann, I., Müller-Newen, G., Schaper, F. & Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334(Pt 2), 297-314 (1998).
Stanke-Labesque, F., Gautier-Veyret, E., Chhun, S., Guilhaumou, R. & French Society of Pharmacology and Therapeutics Inflammation is a major regulator of drug metabolizing enzymes and transporters: consequences for the personalization of drug treatment. Pharmacol. Ther. 215, 107627 (2020).
Oliva-Vilarnau, N., Vorrink, S.U., Ingelman-Sundberg, M. & Lauschke, V.M. A 3D cell culture model identifies Wnt/β-Catenin mediated inhibition of p53 as a critical step during human hepatocyte regenerations. Adv. Sci. (Weinh) 7, 2000248 (2020).
Vorrink, S.U., Zhou, Y., Ingelman-Sundberg, M. & Lauschke, V.M. Prediction of drug-induced hepatotoxicity using long-term stable primary hepatic 3D spheroid cultures in chemically defined conditions. Toxicol. Sci. 163, 655-665 (2018).
Phillips, M.B. et al. Xenobiotic metabolism in alginate-encapsulated primary human hepatocytes over long timeframes. Appl. In vitro Toxicol. 4, 238-247 (2018).
Järvinen, E., Hammer, H.S., Pötz, O., Ingelman-Sundberg, M. & Stage, T.B. 3D spheroid primary human hepatocytes for prediction of cytochrome P450 and drug transporter induction. Clin. Pharmacol. Ther. 113, 1284-1294 (2023).
Ingelman-Sundberg, M. & Lauschke, V.M. 3D human liver spheroids for translational pharmacology and toxicology. Basic Clin. Pharmacol. Toxicol. 130(Suppl 1), 5-15 (2022).
Lauschke, V.M. et al. Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation. Hepatology 64, 1743-1756 (2016).
Lenoir, C. et al. Impact of acute inflammation on cytochromes P450 activity assessed by the Geneva cocktail. Clin. Pharmacol. Ther. 109, 1668-1676 (2021).
De Jong, L.M., Jiskoot, W., Swen, J.J. & Manson, M.L. Distinct effects of inflammation on cytochrome P450 regulation and drug metabolism: lessons from experimental models and a potential role for Pharmacogenetics. Genes (Basel) 11, 1509 (2020).
Pridgeon, C.S., Johansson, I. & Ingelman-Sundberg, M. Response to Rowland and Achour et al. Clin. Pharmacol. Ther. 112, 1155 (2022).
Ridgley, L.A., Anderson, A.E. & Pratt, A.G. What are the dominant cytokines in early rheumatoid arthritis? Curr. Opin. Rheumatol. 30, 207-214 (2018).
Lan, T., Chen, L. & Wei, X. Inflammatory cytokines in cancer: comprehensive understanding and clinical Progress in gene therapy. Cell 10, 100 (2021).
Devaraj, S., Dasu, M.R. & Jialal, I. Diabetes is a proinflammatory state: a translational perspective. Expert Rev. Endocrinol. Metab. 5, 19-28 (2010).
Chung, K.F. & Barnes, P.J. Cytokines in asthma. Thorax 54, 825-857 (1999).
Kato, Y. et al. Human UDP-glucuronosyltransferase (UGT) 2B10 in drug N-glucuronidation: substrate screening and comparison with UGT1A3 and UGT1A4. Drug Metab. Dispos. 41, 1389-1397 (2013).
Harjumäki, R., Pridgeon, C.S. & Ingelman-Sundberg, M. CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ROS, reactive intermediates and lipid overload. Int. J. Mol. Sci. 22, 8221 (2021).
Yang, Q., Humphreys, S.C., Lade, J.M. & Li, A.P. Prolonged cultured human hepatocytes as an in vitro experimental system for the evaluation of potency and duration of activity of RNA therapeutics: demonstration of prolonged duration of gene silencing effects of a GalNAc-conjugated human hypoxanthine phosphoribosyl transferase (HPRT1) siRNA. Biochem. Pharmacol. 189, 114374 (2021).