Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
Drug Metab Dispos. 2013 Jun;41(6):1170-3. doi: 10.1124/dmd.113.051623. Epub 2013 Mar 28.
The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes, such as cytochrome P450, and certain transferases. p38 Mitogen-activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell lines including HepG2 cells. Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR. In the present study, we found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes. siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA. In addition to CYP2B6, anisomycin cotreatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs. Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug-metabolizing enzymes. Our present results suggest that CAR-mediated induction of these enzymes cannot be understood by ligand binding alone because the specificity and magnitude of induction are codetermined by a given cell signaling, such as p38 MAPK; both physiologic and pathophysiological states of cell signaling may have a strong impact in hepatic drug-metabolizing capability during treatments.
组成型激活的芳烃受体 (CAR) 通过激活基因（如细胞色素 P450 和某些转移酶）来调节肝脏的药物代谢。丝裂原活化蛋白激酶 p38 (MAPK) 在人原代肝细胞中高度激活，但在 HepG2 细胞等人肝癌细胞系中几乎不激活。配体结合的 CAR 在人原代肝细胞中诱导 CYP2B6 mRNA 的能力远高于在过表达 CAR 的 HepG2 细胞中。在本研究中，我们发现，anisomycin 激活 p38 MAPK 增强了 CAR 配体在 HepG2 细胞中诱导 CYP2B6 mRNA 的能力，使其达到配体处理的人原代肝细胞中的水平。p38 MAPK 的 siRNA 敲低消除了 anisomycin 协同诱导 CYP2B6 mRNA 的能力。除了 CYP2B6 外，anisomycin 共处理还增强了 CYP2A7 和 CYP2C9 mRNA 的增加，但不增加 CYP3A4 或 UDP-葡糖醛酸基转移酶 1A1 mRNA。因此，激活的 p38 MAPK 是 CAR 配体选择性激活一组编码药物代谢酶的基因所必需的。我们目前的结果表明，CAR 介导的这些酶的诱导不能仅通过配体结合来理解，因为诱导的特异性和幅度由特定的细胞信号转导（如 p38 MAPK）共同决定；细胞信号转导的生理和病理状态可能在治疗期间对肝脏药物代谢能力产生强烈影响。
