{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T21:20:15Z","timestamp":1770153615812,"version":"3.49.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>In drug development, a system for predicting drug metabolism and drug\u2010induced toxicity is necessary to ensure drug safety. Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) is an important drug\u2010metabolizing enzyme expressed in the liver and small intestine, and predicting CYP3A4\u2010mediated drug metabolism and drug\u2010induced toxicity is essential. We previously developed procedures to differentiate human induced pluripotent stem (iPS) cells into hepatocyte\u2010like cells (HLCs) or intestinal epithelial\u2010like cells (IECs) with a fetal phenotype as well as a highly efficient genome editing technology that could enhance the homologous recombination efficiency at any locus, including CYP3A4. By using human iPS cells and our genome editing technology, we generated CYP3A4\u2010knockout (KO) iPS cell\u2010derived HLCs and IECs for the evaluation of CYP3A4\u2010mediated drug metabolism and drug\u2010induced toxicity. CYP3A4 deficiency did not affect pluripotency and hepatic and intestinal differentiation capacities, and CYP3A4 activity was entirely eradicated by CYP3A4 KO. Off\u2010target effects (e.g., inhibition of bile acid excretion) were hardly observed in CYP3A4\u2010KO cells but were observed in CYP3A4 inhibitor\u2010treated (e.g., ketoconazole) cells. To evaluate whether drug\u2010induced hepatotoxicity and enterotoxicity could be predicted using our model, we exposed CYP3A4\u2010KO HLCs and IECs to acetaminophen, amiodarone, desipramine, leflunomide, tacrine, and tolcapone and confirmed that these cells could predict CYP3A4\u2010mediated toxicity. Finally, we examined whether the therapeutic effects of an anti\u2010hepatitis C virus (HCV) drug metabolized by CYP3A4 would be predicted using our model. CYP3A4\u2010KO HLCs were treated with asunaprevir (antiviral drug metabolized by CYP3A4) after HCV infection, and the anti\u2010viral effect was indeed strengthened by CYP3A4 KO. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: We succeeded in generating a novel evaluation system for prediction of CYP3A4\u2010mediated drug metabolism and drug\u2010induced toxicity.<\/jats:p>","DOI":"10.1002\/hep4.1729","type":"journal-article","created":{"date-parts":[[2021,5,6]],"date-time":"2021-05-06T09:26:35Z","timestamp":1620293195000},"page":"1385-1399","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":11,"title":["In Vitro Model for a Drug Assessment of Cytochrome P450 Family 3 Subfamily A Member 4 Substrates Using Human Induced Pluripotent Stem Cells and Genome Editing Technology"],"prefix":"10.1097","volume":"5","author":[{"given":"Sayaka","family":"Deguchi","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiro","family":"Shintani","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Harada","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Environmental Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Institute for Advanced Co\u2010creation Studies, Research Institute for Microbial Diseases,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinori","family":"Takemura","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceutics,Graduate School of Pharmaceutical Sciences,Chiba University,Chiba,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazumasa","family":"Hirata","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Environmental Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kousei","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceutics,Graduate School of Pharmaceutical Sciences,Chiba University,Chiba,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuo","family":"Takayama","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"},{"name":"Center for Induced Pluripotent Stem Cell Research and Application,Kyoto University,Kyoto,Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Mizuguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology,Graduate School of Pharmaceutical Sciences,Osaka University,Osaka,Japan"},{"name":"Laboratory of Hepatocyte Regulation,National Institutes of Biomedical Innovation, Health and Nutrition,Osaka,Japan"},{"name":"Global Center for Medical Engineering and Informatics,Osaka University,Osaka,Japan"},{"name":"Integrated Frontier Research for Medical Science Division of the Institute for Open and Transdisciplinary Research Initiatives,Osaka 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