Slitt A L, Cherrington N J, Dieter M Z, Aleksunes L M, Scheffer G L, Huang W, Moore D D, Klaassen C D
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417, USA.
Mol Pharmacol. 2006 May;69(5):1554-63. doi: 10.1124/mol.105.014571. Epub 2006 Jan 31.
trans-Stilbene oxide (TSO) induces drug metabolizing enzymes in rat and mouse liver. TSO is considered a phenobarbital-like compound because it induces Cyp2B mRNA expression in liver. Phenobarbital increases Cyp2B expression in liver via activation of the constitutive androstane receptor (CAR). The purpose of this study was to determine whether TSO induces gene expression in mouse liver via CAR activation. TSO increased CAR nuclear localization in mouse liver, activated the human Cyp2B6 promoter in liver in vivo, and activated a reporter plasmid that contains five nuclear receptor 1 (NR1) binding sites in HepG2 cells. TSO administration increased expression of Cyp2b10, NAD(P)H:quinone oxidoreductase (Nqo1), epoxide hydrolase, heme oxygenase-1, UDP-glucuronosyl-transferase (Ugt) 1a6 and 2b5, and multidrug resistance-associated proteins (Mrp) 2 and 3 mRNA in livers from male mice. Cyp2b10 and epoxide hydrolase induction by TSO was decreased in livers from CAR-null mice, compared with wild-type mice, suggesting CAR involvement. In contrast, TSO administration induced Nqo1 and Mrp3 mRNA expression equally in livers from wild-type and CAR-null mice, suggesting that TSO induces expression of some genes through a mechanism independent of CAR. TSO increased nuclear staining of the transcription factor Nrf2 in liver, and activated an antioxidant/electrophile response element luciferase reporter construct that was transfected into HepG2 cells. In summary, in mice, TSO increases Cyp2b10 and epoxide hydrolase expression in mice via CAR, and potentially induces Nqo1 and Mrp3 expression via Nrf2. Moreover, our data demonstrate that a single compound can activate both CAR and Nrf2 transcription factors in liver.
反式氧化茋（TSO）可诱导大鼠和小鼠肝脏中的药物代谢酶。TSO被认为是一种类似苯巴比妥的化合物，因为它能诱导肝脏中Cyp2B mRNA的表达。苯巴比妥通过激活组成型雄甾烷受体（CAR）来增加肝脏中Cyp2B的表达。本研究的目的是确定TSO是否通过激活CAR来诱导小鼠肝脏中的基因表达。TSO增加了小鼠肝脏中CAR的核定位，在体内激活了肝脏中的人Cyp2B6启动子，并激活了在HepG2细胞中含有五个核受体1（NR1）结合位点的报告质粒。给予TSO可增加雄性小鼠肝脏中Cyp2b10、NAD（P）H：醌氧化还原酶（Nqo1）、环氧化物水解酶、血红素加氧酶-1、尿苷二磷酸葡萄糖醛酸基转移酶（Ugt）1a6和2b5以及多药耐药相关蛋白（Mrp）2和3 mRNA的表达。与野生型小鼠相比，CAR基因敲除小鼠肝脏中TSO诱导的Cyp2b10和环氧化物水解酶减少，提示CAR参与其中。相反，给予TSO在野生型和CAR基因敲除小鼠肝脏中诱导Nqo1和Mrp3 mRNA表达的程度相同，表明TSO通过一种不依赖于CAR的机制诱导某些基因的表达。TSO增加了肝脏中转录因子Nrf2的核染色，并激活了转染到HepG2细胞中的抗氧化/亲电反应元件荧光素酶报告构建体。总之，在小鼠中，TSO通过CAR增加Cyp2b10和环氧化物水解酶的表达，并可能通过Nrf2诱导Nqo1和Mrp3的表达。此外，我们的数据表明，单一化合物可在肝脏中激活CAR和Nrf2转录因子。
