THE AH RECEPTOR AS A REGULATOR OF HYDROCARBON BIOACTIVITY

多环芳烃(PAH)是一类环境污染物 已知的致癌物质在危险废物场所中浓度较高。 多环芳烃与一种胞浆蛋白--芳香族蛋白结合的近端事件 烃受体(AhR)。带有附件的结合型AhR复合体 分子(ArnT)，转位到细胞核，结合特定的DNA 细胞色素P450IA1(CyPIA1)基因的识别测序和诱导 抄写。由此产生的单加氧酶活性的诱导导致 产生致癌的多环芳烃代谢物。最近，它被展示出来了 暴露于多环芳烃会损害免疫系统、生物系统 负责杀死新形成的肿瘤。这些观察结果举例说明 对多环芳烃的生物和潜在病理反应的广度。我们 还有一些人注意到，多环芳烃可引起多种细胞内变化 包括钙离子通量，蛋白质磷酸化，原癌基因诱导，以及 激素和生长因子受体在似乎是P- 450条独立的信号转导通路。AhR在许多方面的作用 这些细胞内事件之间存在牵连，但尚未得到正式证实。 如果AHR在这些回应中的作用得到确认，那么它将是 预测了AhR活动的水平代表了一个关键的限制 碳氢化合物诱导细胞多途径诱导的因素 激活。在此，我们建议首先检验这一假设 在明确定义的动物系统中操纵AhR活动，最终 评估人类的AhR活性。以下是具体目标 建议。1)培育出携带淋巴细胞的体细胞杂交小鼠 不表达AhR、高水平的AhR或能够结合的突变体AhR 多环芳烃，但不能与DNA识别元件络合； 评价AhR在淋巴细胞PAH反应性中的作用 体细胞杂交小鼠。重点将放在人力资源评估在以下方面的作用 诱导PAH处理的淋巴细胞和其他细胞的凋亡 免疫毒理学终点。它们的反应比较 淋巴细胞到PAH将有助于剖析推测的替代途径 多环芳烃的生物活化。3)推广在这些动物系统中获得的结果 通过评估AhR在人类中的多态性和表达，并预测 特定AhR表型代表分子生物标记物的可能性 人类对多环芳烃的易感性。

Polycyclic aromatic hydrocarbons (PAH) are a class of environmental carcinogens known to occur at high concentrations in hazardous waste sites. A proximal event in PAH binding to a cytosolic protein, the aromatic hydrocarbon receptor (AhR). Ligated AhR complexes with an accessory molecule (ARNT), translocates to the nucleus, binds specific DNA recognition sequences and induces cytochrome P450IA1 (CyPIA1) mRNA transcription. The resulting induction of monooxygenase activity leads to production of carcinogenic PAH metabolites. Recently, it has been shown the PAH exposure compromises the immune system, the biologic system responsible for killing newly formed tumors. These observations exemplify the breadth of biologic and potentially pathologic responses to PAH. We and others have noted that PAH induce a variety of intracellular changes including Ca2+ flux, protein phosphorylation, proto-oncogene induction, and modulation of hormone and growth factor receptors in what appears to be P- 450-independent signal transduction pathways. A role for the AhR in many of these intracellular events has been implicated, but not formally proven. If a role for the AhR in these responses is confirmed, then it would be predicted that the level of AhR activity represents a critical an limiting factor in the induction of multiple pathways of hydrocarbon-induced cell activation. Herein we propose to test this hypothesis initially be manipulating AhR activity in well-defined animal systems and eventually be evaluating AhR activity in humans. The following specific aims have been proposed. 1) To produce somatic hybrid mice which bear lymphocytes expressing no AhR, high levels of AhR, or a mutant AhR capable of binding PAH but incapable of complexing with DNA recognition elements; 2) To evaluate AhR function in the PAH-responsiveness of lymphocytes from these somatic hybrid mice. Emphasis will be placed on the role of the AhR in inducing apoptosis in PAH treated lymphocytes and on other immunotoxicologic endpoints. Comparison of the responses of these lymphocytes to PAH will help dissect the putative alternative pathways of PAH bioactivation. 3) To extend results obtained in these animal systems by evaluating AhR polymorphism and expression in humans and projecting the likelihood that particular AhR phenotypes represent molecular biomarkers for PAH susceptibility in humans.