title: BDE47 induces rat CYP3A1 by targeting the transcriptional regulation of miR-23b.
abstract: Cytochrome P450 3A (CYP3A) is the most abundant CYP450 enzyme in the liver and is involved in the metabolism of over 50% of xenobiotics. Our previous studies revealed that 2,2',4,4'-tetrabromodiphenyl ether (BDE47) could induce rat CYP3A1 expression, but the molecular basis remains unclear. Using in silico analysis, we identified a potential miR-23b recognition element (MRE23b) in the 3'-UTR region of CYP3A1 mRNA, which was verified by the luciferase assay. The miR-23b mimic and inhibitor significantly down- and up-regulated the expression of CYP3A1, respectively. Additionally, BDE47 significantly down-regulated the expression of miR-23b in rats and in hepatic H4IIE cells. Induction or blockage of CYP3A1 by a miR-23b inhibitor or mimic could correspondingly alter BDE47-induced expression of CYP3A1 and cytotoxicity in H4IIE cells. Furthermore, LV-anti-miR-23b significantly decreased endogenous levels of miR-23b and increased the expression and activity of CYP3A1 in rat liver. LV-anti-miR-23b also significantly increased the hydroxylated metabolites of BDE47 (3-OH-BDE47, 4-OH-BDE42, and 4'-OH-BDE49) in rat serum. In conclusion, we first found that BDE47 induced rat CYP3A1 expression by targeting the transcriptional regulation of miR-23b. This study helps provide a better understanding of CYP3A regulation and offers novel clues for the role of miRNAs in the metabolism and distribution of environmental pollutants.
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|Key Laboratory of Pediatrics, Nanjing Children's Hospital Affiliated to Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, P. R. China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing 210029, P. R. China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Ji
authors.affiliation: Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211166, P. R. China.
authors.forename: Hongbao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, 1207 Gilbert Drive, Lubbock, TX 79416, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Cromie
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing 210029, P. R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing 210029, P. R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing 210029, P. R. China.
authors.forename: Yongquan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, 1207 Gilbert Drive, Lubbock, TX 79416, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Gao
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, P. R. China.|State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Rd., Nanjing 210029, P. R. China.
authors.forename: Shou-Lin
authors.initials: SL
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000070416:Antagomirs / Q000494:pharmacology; D002460:Cell Line; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055768:Halogenated Diphenyl Ethers / Q000378:metabolism / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020413:3' Untranslated Regions; D000070416:Antagomirs; D051544:Cytochrome P-450 CYP3A; D055768:Halogenated Diphenyl Ethers; D035683:MicroRNAs; D034741:RNA, Small Interfering; C000590974:MIRN23a microRNA, rat; C511295:2,2',4,4'-tetrabromodiphenyl ether; C465138:Cyp3a23-3a1 protein, rat