Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in human liver and kidney in vitro models
Toxicology in Vitro, vol. 104, pp. 106010
Abstract
The potent dihydroorotate dehydrogenase (DHODH) inhibitor brequinar has been investigated as an anticancer, immunosuppressive, and antiviral pharmaceutical agent. However, its toxicity is still poorly understood. We investigated the cellular responses of primary human hepatocytes (PHH) and telomerase-immortalised human renal proximal tubular epithelial cells (RPTEC/TERT1) after a single 24-h exposure up to 100 μM brequinar. Additionally, RPTEC/TERT1 cells underwent repeated daily exposure for five consecutive days at 0.3, 3, and 20 μM. Transcriptomic analysis revealed that PHH were less sensitive to brequinar treatment than RPTEC/TERT1 cells. Upregulation of various phase I and II drug-metabolising enzymes, particularly Cytochrome P450 (CYP) 1 A and 3 A enzymes, in PHH suggests potential detoxification. Furthermore, brequinar exposure led to a significant upregulation of several stress response pathways in PHH and RPTEC/TERT1 cells, including the unfolded protein response, Nrf2, p53, and inflammatory responses. RPTEC/TERT1 cells exhibited greater sensitivity to brequinar at 0.3 μM with repeated exposure compared to a single exposure. Furthermore, brequinar could impair the mitochondrial respiration of RPTEC/TERT1 cells after 24 h. This study provides new insights into the differential responses of PHH and RPTEC/TERT1 cells in response to brequinar exposure and highlights the biological relevance of implementing repeated dosing regimens in in vitro studies.
Authors 14
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Affiliation as printed
Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands. Electronic address: t.meijer@vu.nl
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Bas ter Braak Aachen
Affiliation as printed
Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands; Toxys B.V., Leiden Bioscience Park, 2342 DH Oegstgeest, the Netherlands
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Liesanne Loonstra-Wolters Aachen
Affiliation as printed
Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands; Toxys B.V., Leiden Bioscience Park, 2342 DH Oegstgeest, the Netherlands
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Affiliation as printed
Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands. Electronic address: s.j.kunnen@lacdr.leidenuniv.nl
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Affiliation as printed
Certara - Simcyp Division, Sheffield, United Kingdom. Electronic address: barira.islam@certara.com
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Affiliation as printed
In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Universitaetsstr. 10, 78464 Konstanz, Germany
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Affiliation as printed
Certara - Simcyp Division, Sheffield, United Kingdom
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Affiliation as printed
Certara - Simcyp Division, Sheffield, United Kingdom
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Affiliation as printed
Syngenta Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
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Edelweiss Connect (Switzerland)
Affiliation as printed
Edelweiss Connect GmbH, Technology Park Basel, Hochbergerstrasse 60C, 4057 Basel, Switzerland. Electronic address: Barry.Hardy@edelweissconnect.com
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Affiliation as printed
In Vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Universitaetsstr. 10, 78464 Konstanz, Germany
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Affiliation as printed
Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands. Electronic address: water_b@lacdr.leidenuniv.nl
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Affiliation as printed
Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands. Electronic address: p.jennings@vu.nl
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Affiliation as printed
Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands. Electronic address: a.wilmes@vu.nl
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