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Accordingly, POR-centric NADPH-supplemented human liver microsomes (HLM) and recombinant CYP-POR systems complement human hepatocytes (HH) as drug-metabolism models. However, HH may exhibit inexplicably lower CYP activities relative to NADPH-HLM, particularly for CYP3A4-substrates. Here, we show the phenomenon can manifest as disparate CYP phenotyping in which NADPH-HLM and recombinant CYP-POR systems incorrectly identify CYP3A4 while HH accurately assign the main-metabolising CYP exemplified by CYP1A2 for savolitinib. Mechanistically, we serendipitously discover that HH CYP3A4-mediated midazolam-metabolism is increased by gefitinib and find that this can only be recapitulated in non-canonical Cyt\n                    <jats:italic>b<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>5<\/jats:italic>\n                    <\/jats:sub>\n                    R-dependent NADH-HLM and recombinant CYP3A4-Cyt\n                    <jats:italic>b<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>5<\/jats:italic>\n                    <\/jats:sub>\n                    R. We conclude that Cyt\n                    <jats:italic>b<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>5<\/jats:italic>\n                    <\/jats:sub>\n                    R is important for HH-CYP3A4 and show HH-consistent CYP3A4-activities in NADH-HLM. Imaging NADH\/NADPH in hepatocytes shows equivalent concentrations suggesting CYP redox-partnerships are cofactor-independent and likely influenced by protein-protein interactions as mimicking the dense-intracellular protein using albumin recapitulates HH savolitinib-metabolism in HLM.\n                  <\/jats:p>","DOI":"10.1038\/s42003-025-08903-1","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:34:06Z","timestamp":1762432446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A mismatch in enzyme-redox partnerships underlies divergent cytochrome P450 activities between human hepatocytes and microsomes"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1483-2161","authenticated-orcid":false,"given":"Tashinga E.","family":"Bapiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8949-6238","authenticated-orcid":false,"given":"Thomas S.","family":"Blacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5440-6802","authenticated-orcid":false,"given":"Alexandra L.","family":"Orton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6290-5329","authenticated-orcid":false,"given":"Niresh","family":"Hariparsad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys D. 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