{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T22:13:47Z","timestamp":1785363227999,"version":"3.55.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T00:00:00Z","timestamp":1552003200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"},{"start":{"date-parts":[[2020,3,8]],"date-time":"2020-03-08T00:00:00Z","timestamp":1583625600000},"content-version":"am","delay-in-days":366,"URL":"http:\/\/rsc.li\/journals-terms-of-use"}],"content-domain":{"domain":["rsc.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Organotin anticancer agent di-n-butyl-di-(4-chlorobenzohydroxamato)tin(iv) (DBDCT) exerted an inhibitory effect on its major metabolic enzyme cytochrome CYP3A. But whether hepatic drug-metabolizing enzymes and their regulatory nuclear receptors including pregnane PXR and constitutive androstane CAR binding with retinoid receptor RXR as a heterodimer are involved in the DBDCT-mediated regulation of CYP3A remains unclear. This study was undertaken to determine the mechanisms responsible for the effects of DBDCT on CYP3A suppression, focusing on the PXR-mediated and NF-\u03baB pathways. The results indicated DBDCT suppressed CYP3A expression by inhibiting CAR expression. But what's interesting is, both protein and mRNA of PXR increased with increasing DBDCT. A further exploration, dual luciferase reporter gene analysis, clarified that DBDCT induced CYP3A expression elevation via the PXR-mediated pathway and this induction was countered by activation of NF-\u03baB, which played a pivotal role in suppression of CYP3A through disrupting the association of the PXR\u2013RXR\u03b1 complex with DNA sequences by EMSA. PXR-mediated CYP3A expression was similarly demonstrated by RNAi. As expected, expression of CYP3A and its mRNA levels were reduced by DBDCT only in NF-\u03baB(+\/+) but not in NF-\u03baB(\u2212\/\u2212) cells. The inductive effect of DBDCT on CYP3A4 mRNA was enhanced in PXR shRNA-transfected cells but weakened in the ip65 group, which showed both PXR up-regulated CYP3A expression and NF-\u03baB p65 activation directly contributed to CYP3A inhibition. In conclusion, activated NF-\u03baB by DBDCT interacts directly with the DNA-binding domain of PXR, and disrupts the binding between the PXR\u2013RXR dimer, thereby affecting the regulatory process for CYP3A transcription and, therefore, leading to a decrease of the expression of the PXR-regulated CYP3A.<\/jats:p>","DOI":"10.1039\/c8mt00361k","type":"journal-article","created":{"date-parts":[[2019,3,8]],"date-time":"2019-03-08T10:55:41Z","timestamp":1552042541000},"page":"936-948","update-policy":"https:\/\/doi.org\/10.1039\/rsc_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Organotin compound DBDCT induces CYP3A suppression through NF-\u03baB-mediated repression of PXR activity"],"prefix":"10.1093","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7494-8289","authenticated-orcid":false,"given":"Yunlan","family":"Li","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Mai","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingshan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Science, Shanxi Medical University, Taiyuan 030001, P. R. China"},{"name":"Shanxi University of Chinese Medicine, Jinzhong 030619, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,8]]},"reference":[{"issue":"1\u20132","key":"2021121516074245600_cit1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0009-2797(80)90075-7","article-title":"Investigations into the antitumour activity of organotin compounds","volume":"32","author":"Crowe","year":"1980","journal-title":"Chem. \u2013 Biol. Interact."},{"issue":"1","key":"2021121516074245600_cit2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/aoc.590020106","article-title":"The in vitro antiherpes activity of some selected antitumor organotin compounds","volume":"2","author":"Ward","year":"2010","journal-title":"Appl. Organomet. 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