Baylor College of Medicine, 1102 Bates Street, Suite 530.01, Houston, TX 77030, USA.
J Pharmacol Exp Ther. 2010 Nov;335(2):369-79. doi: 10.1124/jpet.110.171173. Epub 2010 Aug 23.
The cytochrome P4501A (CYP1A) enzymes play important roles in the metabolic activation and detoxification of numerous environmental carcinogens, including polycyclic aromatic hydrocarbons (PAHs). In this study, we tested the hypothesis that hepatic CYP1A2 differentially regulates mouse hepatic and pulmonary CYP1A1 expression and suppresses transcriptional activation of human CYP1A1 (hCYP1A1) promoter in response to 3-methylcholanthrene (MC) in vivo. Administration of wild-type (WT) (C57BL/6J) or Cyp1a2-null mice with a single dose of MC (100 μmol/kg i.p.) caused significant increases in hepatic CYP1A1/1A2 activities, apoprotein content, and mRNA levels 1 day after carcinogen withdrawal compared with vehicle-treated controls. The induction persisted in the WT, but not Cyp1a2-null, animals, for up to 15 days. In the lung, MC caused persistent CYP1A1 induction for up to 8 days in both genotypes, with Cyp1a2-null mice displaying a greater extent of CYP1A1 expression. It is noteworthy that MC caused significant augmentation of human CYP1A1 promoter activation in transgenic mice expressing the hCYP1A1 and the reporter luciferase gene on a Cyp1a2-null background, compared with transgenic mice on the WT background. In contrast, the mouse endogenous hepatic, but not pulmonary, persistent CYP1A1 expression was repressed by MC in the hCYP1A1-Cyp1a2-null mice. Liquid chromatography-mass spectrometry experiments showed that CYP1A2 catalyzed the formation of 1-hydroxy-3-MC and/or 2-hydroxy-3-MC, a metabolite that may contribute to the regulation of CYP1A1 expression. In conclusion, the results suggest that CYP1A2 plays a pivotal role in the regulation of hepatic and pulmonary CYP1A1 by PAHs, a phenomenon that potentially has important implications for PAH-mediated carcinogenesis.
细胞色素 P4501A（CYP1A）酶在许多环境致癌物质的代谢激活和解毒中发挥重要作用，包括多环芳烃（PAHs）。在这项研究中，我们测试了以下假设：肝 CYP1A2 以不同的方式调节小鼠肝和肺 CYP1A1 的表达，并在体内对 3-甲基胆蒽（MC）做出反应，抑制人 CYP1A1（hCYP1A1）启动子的转录激活。给予野生型（WT）（C57BL/6J）或 Cyp1a2-/-小鼠单次 MC（100μmol/kg ip）后，与载体处理的对照组相比，在致癌物去除后 1 天，肝 CYP1A1/1A2 活性、载脂蛋白含量和 mRNA 水平显著增加。这种诱导在 WT 中持续存在，但在 Cyp1a2-/-动物中持续 15 天。在肺中，MC 在两种基因型中持续诱导 CYP1A1 长达 8 天，Cyp1a2-/-小鼠显示出更大程度的 CYP1A1 表达。值得注意的是，MC 引起了 hCYP1A1 启动子在表达 hCYP1A1 和报告基因 luciferase 的转基因小鼠中的显著激活，该小鼠在 Cyp1a2-/-背景下，与在 WT 背景下的转基因小鼠相比。相比之下，在 hCYP1A1-Cyp1a2-/-小鼠中，MC 抑制了人 CYP1A1 的肝内但非肺内持久表达。液相色谱-质谱实验表明，CYP1A2 催化了 1-羟基-3-MC 和/或 2-羟基-3-MC 的形成，这可能是调节 CYP1A1 表达的一种代谢物。总之，这些结果表明，CYP1A2 在 PAHs 对肝和肺 CYP1A1 的调节中发挥着关键作用，这一现象可能对 PAH 介导的致癌作用具有重要意义。
