The Pennsylvania State University, University Park, PA 16802, USA.
Mol Pharmacol. 2010 Feb;77(2):247-54. doi: 10.1124/mol.109.061788. Epub 2009 Nov 10.
The concept of selective receptor modulators has been established for the nuclear steroid hormone receptors. Such selective modulators have been used therapeutically with great success in the treatment of cancer. However, this concept has not been examined with regard to the aryl hydrocarbon receptor (AHR) because of the latent toxicity commonly associated with AHR activation. AHR-mediated toxicity is primarily derived from AHR binding to its dioxin response element (DRE) and driving expression of CYP1 family members, which have the capacity to metabolize procarcinogens to genotoxic carcinogens. Recent evidence using a non-DRE binding AHR mutant has established the DRE-independent suppression of inflammatory markers by the AHR. We wished to determine whether such DRE-independent repression with wild-type AHR could be dissociated from canonical DRE-dependent transactivation in a ligand-dependent manner and, in doing so, prove the concept of a selective AHR modulator (SAhRM). Here, we identify the selective estrogen receptor (ER) modulator Way-169916 as a dually selective modulator, binding both ER and AHR. Inflammatory gene expression associated with the cytokine-inducible acute-phase response (e.g., SAA1 and CRP) are diminished by Way-169916 in an AHR-dependent manner. Furthermore, activation of AHR by Way-169916 fails to stimulate canonical DRE-driven AHR-mediated CYP1A1 expression, thus eliminating the potential for AHR-mediated genotoxic stress. Such anti-inflammatory activity in the absence of DRE-mediated expression fulfills the major criteria of an SAhRM, which suggests that selective modulation of AHR is possible and renders the AHR a therapeutically viable drug target for the amelioration of inflammatory disease.
核甾体激素受体的选择性受体调节剂的概念已经确立。在癌症治疗中，这类选择性调节剂已被成功地用于治疗。然而，由于与 AHR 激活相关的潜在毒性，尚未对芳烃受体（AHR）进行这种概念的检验。AHR 介导的毒性主要源于 AHR 与二恶英反应元件（DRE）结合并驱动 CYP1 家族成员的表达，该家族成员具有将前致癌物代谢为遗传毒性致癌物的能力。最近使用非 DRE 结合 AHR 突变体的证据确立了 AHR 对炎症标志物的非 DRE 依赖性抑制作用。我们希望确定野生型 AHR 是否可以以配体依赖性的方式与经典的 DRE 依赖性反式激活分离，从而证明选择性 AHR 调节剂（SAhRM）的概念。在这里，我们确定选择性雌激素受体（ER）调节剂 Way-169916 是一种双重选择性调节剂，既结合 ER 又结合 AHR。细胞因子诱导的急性期反应相关的炎症基因表达（例如 SAA1 和 CRP）以 AHR 依赖性方式被 Way-169916 降低。此外，Way-169916 激活 AHR 不能刺激经典的 DRE 驱动的 AHR 介导的 CYP1A1 表达，从而消除了 AHR 介导的遗传毒性应激的可能性。在没有 DRE 介导的表达的情况下的抗炎活性满足了 SAhRM 的主要标准，这表明 AHR 的选择性调节是可能的，并且使 AHR 成为改善炎症性疾病的治疗可行的药物靶标。
