Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160-7417, USA.
Drug Metab Dispos. 2012 Jul;40(7):1366-79. doi: 10.1124/dmd.112.045112. Epub 2012 Apr 11.
The transcription factors aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor α (PPARα), and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate genes encoding drug-metabolizing enzymes and transporters in livers of mice after chemical activation. However, the specificity of their transcriptional regulation has not been determined systematically in vivo. The purpose of this study was to identify genes encoding drug-metabolizing enzymes and transporters altered by chemical activators in a transcription factor-dependent manner using wild-type and transcription factor-null mice. Chemical activators were administered intraperitoneally to mice once daily for 4 days. Livers were collected 24 h after the final dose, and total RNA was isolated for mRNA quantification of cytochromes P450, NAD(P)H quinone oxidoreductase 1 (Nqo1), aldehyde dehydrogenases (Aldhs), glutathione transferases (Gsts), sulfotransferases (Sults), UDP-glucuronosyltransferases (Ugts), organic anion-transporting polypeptides (Oatps), and multidrug resistance-associated proteins (Mrps). Pharmacological activation of each transcription factor leads to mRNA induction of drug metabolic and transport genes in livers of male and female wild-type mice, but no change in null mice: AhR (Cyp1a2, Nqo1, Aldh7a1, Ugt1a1, Ugt1a6, Ugt1a9, Ugt2b35, Sult5a1, Gstm3, and Mrp4), CAR (Cyp2b10, Aldh1a1, Aldh1a7, Ugt1a1, Ugt2b34, Sult1e1, Sult3a1, Sult5a1, Papps2, Gstt1, Gsta1, Gsta4, Gstm1-4, and Mrp2-4), PXR (Cyp3a11, Ugt1a1, Ugt1a5, Ugt1a9, Gsta1, Gstm1-m3, Oatp1a4, and Mrp3), PPARα (Cyp4a14, Aldh1a1, mGst3, Gstm4, and Mrp4), and Nrf2 (Nqo1, Aldh1a1, Gsta1, Gsta4, Gstm1-m4, mGst3, and Mrp3-4). Taken together, these data reveal transcription factor specificity and overlap in regulating hepatic drug disposition genes by chemical activators. Coordinated regulation of phase I, phase II, and transport genes by activators of transcription factors can have implications in development of pharmaceuticals as well as risk assessment of environmental contaminants.
转录因子芳香烃受体 (AhR)、细胞色素 P450 家族 1 亚家族 A 成员 1 (CYP1A1)、细胞色素 P450 家族 2 亚家族 B 成员 10 (CYP2B10)、细胞色素 P450 家族 2 亚家族 E 成员 1 (CYP2E1)、细胞色素 P450 家族 3 亚家族 A 成员 4 (CYP3A11)、细胞色素 P450 家族 4 亚家族 A 成员 14 (CYP4A14)、组成型雄烷受体 (CAR)、孕烷 X 受体 (PXR)、过氧化物酶体增殖物激活受体 α (PPARα) 和核因子红细胞 2 相关因子 2 (Nrf2) 调节化学激活后小鼠肝脏中药物代谢酶和转运蛋白的基因表达。然而，它们的转录调控特异性尚未在体内系统确定。本研究的目的是使用野生型和转录因子缺失型小鼠，鉴定化学激活剂以转录因子依赖性方式改变的药物代谢酶和转运蛋白编码基因。化学激活剂每天腹膜内给药一次，共 4 天。最后一次给药后 24 小时收集肝脏，分离总 RNA 用于细胞色素 P450、NAD(P)H 醌氧化还原酶 1 (Nqo1)、醛脱氢酶 (Aldhs)、谷胱甘肽 S-转移酶 (Gsts)、磺基转移酶 (Sults)、尿苷二磷酸葡萄糖醛酸转移酶 (Ugts)、有机阴离子转运多肽 (Oatps) 和多药耐药相关蛋白 (Mrps) 的 mRNA 定量。每种转录因子的药理学激活都会导致雄性和雌性野生型小鼠肝脏中药物代谢和转运基因的 mRNA 诱导，但在缺失型小鼠中没有变化：AhR（Cyp1a2、Nqo1、Aldh7a1、Ugt1a1、Ugt1a6、Ugt1a9、Ugt2b35、Sult5a1、Gstm3 和 Mrp4）、CAR（Cyp2b10、Aldh1a1、Aldh1a7、Ugt1a1、Ugt2b34、Sult1e1、Sult3a1、Sult5a1、Papps2、Gstt1、Gsta1、Gsta4、Gstm1-4 和 Mrp2-4）、PXR（Cyp3a11、Ugt1a1、Ugt1a5、Ugt1a9、Gsta1、Gstm1-m3、Oatp1a4 和 Mrp3）、PPARα（Cyp4a14、Aldh1a1、mGst3、Gstm4 和 Mrp4）和 Nrf2（Nqo1、Aldh1a1、Gsta1、Gsta4、Gstm1-m4、mGst3 和 Mrp3-4）。综上所述，这些数据揭示了转录因子在化学激活剂调节肝脏药物处置基因方面的特异性和重叠。转录因子激活剂对 I 相、II 相和转运基因的协调调节可能对药物开发以及环境污染物的风险评估具有重要意义。
