{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T21:07:42Z","timestamp":1777496862523,"version":"3.51.4"},"reference-count":54,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CH"],"published-print":{"date-parts":[[2021,10,6]]},"abstract":"<jats:p>Cell-based in vitro liver models are an important tool in the development and evaluation of new drugs in pharmacological and toxicological drug assessment. Hepatic microsomal enzyme complexes, consisting of cytochrome P450 oxidoreductase (CPR) and cytochrome P450 monooxygenases (CYPs), play a decisive role in catalysing phase-1 biotransformation of pharmaceuticals and xenobiotics. For a comprehensive understanding of the phase-1 biotransformation of drugs, the availability of well-characterized substances for the targeted modulation of in vitro liver models is essential. In this study, we investigated diphenyleneiodonium (DPI) for its ability to inhibit phase-1 enzyme activity and further its toxicological profile in an in vitro HepG2 cell model with and without recombinant expression of the most important drug metabolization enzyme CYP3A4. Aim of the study was to identify effective DPI concentrations for CPR\/CYP activity modulation and potentially associated dose and time dependent hepatotoxic effects. The cells were treated with DPI doses up to 5,000nM (versus vehicle control) for a maximum of 48 h and subsequently examined for CYP3A4 activity as well as various toxicological relevant parameters such as cell morphology, integrity and viability, intracellular ATP level, and proliferation. Concluding, the experiments revealed a time- and concentration-dependent DPI mediated partial and complete inhibition of CYP3A4 activity in CYP3A4 overexpressing HepG2-cells (HepG2-CYP3A4). Other cell functions, including ATP synthesis and consequently the proliferation were negatively affected in both in vitro cell models. Since neither cell integrity nor cell viability were reduced, the effect of DPI in HepG2 can be assessed as cytostatic rather than cytotoxic.<\/jats:p>","DOI":"10.3233\/ch-219117","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T14:06:40Z","timestamp":1630418800000},"page":"231-243","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of phase-1 biotransformation and cytostatic effects of diphenyleneiodonium on hepatoblastoma cell line HepG2 and a CYP3A4-overexpressing HepG2 cell clone"],"prefix":"10.1177","volume":"79","author":[{"given":"Christian","family":"Schulz","sequence":"first","affiliation":[{"name":"Fraunhofer Project Group PZ-Syn, Fraunhofer Institute for Cell Therapy and Immunology, Branch Bioanalytics and Bioprocesses (IZI-BB), Potsdam, Germany, located at the Institute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedrich","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan-Heiner","family":"K\u00fcpper","sequence":"additional","affiliation":[{"name":"Fraunhofer Project Group PZ-Syn, Fraunhofer Institute for Cell Therapy and Immunology, Branch Bioanalytics and Bioprocesses (IZI-BB), Potsdam, Germany, located at the Institute of Biotechnology, Brandenburg University of Technology Cottbus-Senftenberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","reference":[{"issue":"1","key":"10.3233\/CH-219117_ref1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep25187","article-title":"Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver 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