Germolec D R, Henry E C, Maronpot R, Foley J F, Adams N H, Gasiewicz T A, Luster M I
Environmental Immunology and Neurobiology Section, Naitonal Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709, USA.
Toxicol Appl Pharmacol. 1996 Mar;137(1):57-66. doi: 10.1006/taap.1996.0057.
The immune system is a primary target for toxic insult by a number of drugs and environmental chemicals, many of which require activation to toxic metabolites by drug-metabolizing enzymes. We compared the induction of drug-metabolizing enzymes, including cytochrome P450 1A1 (CYP1A1) and aldehyde dehydrogenase (ALDH), in lymphoid tissues of F344 rats following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). ALDH was induced in both the spleen and the thymus after TCDD treatment, with maximal expression at 9 and 15 days, respectively. Thymic microsomal preparations from TCDD-treated animals expressed elevated levels of inducible CYP1A1 as compared to microsomes from the spleens of treated animals or tissues from control rats. TCDD treatment also resulted in increased ethoxyresorufin-O-deethylase (EROD) activity in the thymus. There were no detectable mRNA transcripts for CYP1A1 in peripheral blood or splenic lymphocytes from treated animals; however, CYP1A1 transcripts were induced in isolated thymocytes, whole spleen, and whole thymus. In vitro exposure to TCDD did not result in induction of immunoreactive CYP1A1 in thymocytes unless simultaneously activated with the mitogen, phytohemagglutinin (PHA). Immunohistochemical localization of CYP1A1 in immune tissues indicated that cells other than the lymphoid populations are responsible for the increased CYP1A1 expression. The pattern of CYP1A1 induction was related to the expression of the Ah receptor (AhR) in immune tissues. Western blot analyses demonstrated less AhR present in peripheral blood lymphoid cells and spleen, as compared to whole tissues. These studies indicate that while drug-metabolizing enzymes are present in immune tissues, the induction of enzymes is selective in different lymphoid cells.
免疫系统是许多药物和环境化学物质毒性损伤的主要靶点，其中许多物质需要通过药物代谢酶激活才能转化为毒性代谢产物。我们比较了2,3,7,8-四氯二苯并对二恶英（TCDD）处理后F344大鼠淋巴组织中药物代谢酶的诱导情况，这些酶包括细胞色素P450 1A1（CYP1A1）和醛脱氢酶（ALDH）。TCDD处理后，脾脏和胸腺中的ALDH均被诱导，分别在第9天和第15天达到最大表达。与处理动物脾脏或对照大鼠组织的微粒体相比，TCDD处理动物的胸腺微粒体制剂中可诱导的CYP1A1水平升高。TCDD处理还导致胸腺中乙氧基异吩恶唑酮-O-脱乙基酶（EROD）活性增加。处理动物的外周血或脾淋巴细胞中未检测到CYP1A1的mRNA转录本；然而，在分离的胸腺细胞、整个脾脏和整个胸腺中诱导出了CYP1A1转录本。体外暴露于TCDD不会导致胸腺细胞中免疫反应性CYP1A1的诱导，除非同时用丝裂原植物血凝素（PHA）激活。免疫组织化学定位显示，免疫组织中CYP1A1表达增加的原因是淋巴细胞以外的细胞。CYP1A1的诱导模式与免疫组织中芳烃受体（AhR）的表达有关。蛋白质免疫印迹分析表明，与整个组织相比，外周血淋巴细胞和脾脏中的AhR较少。这些研究表明，虽然免疫组织中存在药物代谢酶，但不同淋巴细胞中酶的诱导具有选择性。
