THE AH RECEPTOR AS A REGULATOR OF HYDROCARBON BIOACTIVITY

多环芳烃（PAH）是一类环境污染物， 已知在危险废物场中存在高浓度的致癌物。 PAH与胞质蛋白质结合的近端事件，芳香族 碳氢化合物受体（AhR）。 具有辅助物的连接的AhR复合物 分子（ARNT），易位到细胞核，结合特定的DNA 识别序列并诱导细胞色素P450 IA 1（CyPIA 1）mRNA 转录。 单加氧酶活性的诱导导致 产生致癌的PAH代谢物。 最近，有证据表明， 接触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 PAH的生物学和潜在病理学反应的广度。 我们 和其他人已经注意到PAH诱导多种细胞内变化， 包括Ca 2+流动、蛋白磷酸化、原癌基因诱导， 激素和生长因子受体的调节似乎是P- 450-独立的信号转导通路。 在许多情况下，AhR的作用 这些细胞内的事件已经牵连，但没有正式证实。 如果AhR在这些反应中的作用得到证实，那么它将是 预测AhR活性水平代表了一个关键的限制， 烃诱导细胞多途径诱导因子 activation. 在这里，我们建议测试这一假设最初是 在明确的动物系统中操纵AhR活性， 评估人类的AhR活性。 以下具体目标已经 提出了 1)产生携带淋巴细胞的体细胞杂交小鼠 不表达AhR、表达高水平AhR或表达能够结合 PAH，但不能与DNA识别元件络合; 2） 评估AhR在淋巴细胞PAH反应性中的功能， 体细胞杂交小鼠 重点将放在人权高专办在以下方面的作用： 在PAH处理的淋巴细胞中诱导细胞凋亡， 免疫毒理学终点。 这些反应的比较 淋巴细胞的PAH将有助于解剖假定的替代途径， PAH生物活化。 3)为了扩展在这些动物系统中获得的结果， 通过评估人类AhR多态性和表达， 特定AhR表型代表分子生物标志物的可能性 对PAH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.