{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:35:33Z","timestamp":1762101333935,"version":"3.40.3"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2012,12,1]],"date-time":"2012-12-01T00:00:00Z","timestamp":1354320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>We previously established HepG2-GS-3A4, a cell line from hepatoblastoma with overexpression of human CYP3A4 and glutamine synthetase (GS). We further reported that these cells can be applied for screening inhibitors of CYP3A4 in vitro. The purpose of this study was to determine whether our CYP3A4-overexpresed cell could be applied to evaluate mechanisms of CYP3A4 inhibition by 6\u2032,7\u2032-dihydroxybergamottin (DHB), which is one of the major furanocoumarins in grapefruit juice, by using these cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nifedipine oxidation, activity and protein expression of NADPH-cytochrome reductase (POR) of HepG2-GS-3A4 cell were measured. CO-binding spectrumassay in microsomal fraction of the cells was also evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key findings<\/jats:title><jats:p>DHB and ketoconazole, a well-known inhibitor of CYP3A4, inhibited nifedipine oxidation in a concentration-dependent manner. DHB at a concentration of 3.0 \u00b5m, sufficient to inhibit the nifedipine oxidation, decreased POR activity; however, ketoconazole at a concentration of 0.9 \u00b5m, sufficient to inhibit the oxidation, did not affect the activity. The expression of POR protein in HepG2-GS-3A4 cells was not changed by either DHB or ketoconazole. The expression of CYP3A4 mRNA and protein was not changed by the addition of DHB or ketoconazole. DHB also reduced the absorption rate at 450 nm in a CO-binding spectrum assay without alteration of the wavelength of maximum absorption. The mean absorption value at 450 nm slightly decreased with ketoconazole; however, the difference was not significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We concluded that inhibition of CYP3A4 activity by DHB includes the inhibition of POR activity. HepG2-GS-3A4 might be a good tool to evaluate the mechanisms.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.2042-7158.2012.01562.x","type":"journal-article","created":{"date-parts":[[2012,8,3]],"date-time":"2012-08-03T18:28:05Z","timestamp":1344018485000},"page":"1715-1721","source":"Crossref","is-referenced-by-count":6,"title":["Inhibition of CYP3A4 by 6\u2032,7\u2032-dihydroxybergamottin in human CYP3A4 over-expressed hepG2 cells"],"prefix":"10.1093","volume":"64","author":[{"given":"Nobutaka","family":"Araki","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology, Jichi Medical University , Tochigi,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuichi","family":"Tsuruoka","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Jichi Medical University , Tochigi,","place":["Japan"]},{"name":"Department of Nephrology, Faculty of Medicine, University of Tsukuba , Ibaraki,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gohki","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Jichi Medical University , Tochigi,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayato","family":"Yanagihara","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Jichi Medical University , Tochigi,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Omasa","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Graduate School of Engineering, Osaka University , Osaka,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Enosawa","sequence":"additional","affiliation":[{"name":"Department of Innovative Surgery, National Research Institute for Child Health and Development , Tokyo,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasushi","family":"Yamazoe","sequence":"additional","affiliation":[{"name":"Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University , Sendai,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akio","family":"Fujimura","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Jichi Medical University , Tochigi,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,12,1]]},"reference":[{"key":"2024103013313211200_cit1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/0009-9236(95)90068-3","article-title":"Interaction between grapefruit juice and midazolam in humans","volume":"58","author":"Kupferschmidt","year":"1995","journal-title":"Clin Pharmacol Ther"},{"key":"2024103013313211200_cit2","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/0140-6736(91)90872-M","article-title":"Interaction of citrus juices with felodipine and nifedipine","volume":"337","author":"Bailey","year":"1991","journal-title":"Lancet"},{"key":"2024103013313211200_cit3","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/00008571-199710000-00008","article-title":"Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction","volume":"7","author":"Fukuda","year":"1997","journal-title":"Pharmacogenetics"},{"key":"2024103013313211200_cit4","first-page":"1228","article-title":"Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. 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