Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor
Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor
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DOI：
10.1073/pnas.1118467109
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发表时间：
2012-03-20
影响因子：
11.1
通讯作者：
Rannug, Agneta
中科院分区：
文献类型：
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作者：
Wincent, Emma;Bengtsson, Johanna;Rannug, Agneta
改变系统水平的6-甲酰吲哚并[3，2-B]咔唑（FICZ），一个神秘的内源性配体的芳烃受体（AHR），可以解释不良生理反应引起的小自然和人为分子以及氧化应激和光。我们在这里证明，几种不同的化合物可以抑制FICZ的代谢，从而破坏细胞色素P4501系统和其他蛋白质的表达受AHR调节的自动调节反馈控制。FICZ是AHR的最紧密结合的内源性激动剂，也是细胞色素CYP 1A 1/1A 2和1B 1的理想底物，因此也参与了保持自身稳态浓度较低的自动调节回路。在非常低的浓度下，FICZ影响昼夜节律、对UV光的响应、与促炎和抗炎过程相关的稳态以及基因组稳定性。在这里，我们证明，如果其代谢清除率受损，该化合物在细胞培养基中的飞摩尔背景水平足以上调CYP 1A 1 mRNA和酶活性。氧化剂UVB照射和过氧化氢以及模型AHR拮抗剂3 '-甲氧基-4'-硝基黄酮均抑制FICZ或2，3，7，8-四氯二苯并-p-二恶英对CYP 1A 1酶活性的诱导，从而随后升高细胞内FICZ水平并激活AHR。总之，这些发现支持AHR激活的间接机制，表明低亲和力分子的AHR激活实际上可能反映了FICZ代谢的抑制，并对报告的AHR混杂性提出了质疑。因此，我们提出，通过抑制CYP 1延长AHR活性的诱导干扰FICZ水平的反馈调节，具有潜在的有害后果。
Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3'-methoxy-4'-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.