Lesca P, Peryt B, Larrieu G, Alvinerie M, Galtier P, Daujat M, Maurel P, Hoogenboom L
Laboratoire de Pharmacologie-Toxicologie, INRA, Toulouse, France.
Biochem Biophys Res Commun. 1995 Apr 17;209(2):474-82. doi: 10.1006/bbrc.1995.1526.
Benzimidazole derivatives are potent inducers of CYP1A1 in rabbit and human hepatocytes, but apparently do not bind the AH receptor. To resolve this paradoxical behaviour, studies have been concerned with the question of whether an alternative ligand-independent mechanism could explain the activation of the AH receptor. From experiments in cultured rabbit hepatocytes we show that benzimidazoles bind early and transiently to an unknown protein. Moreover, they are able to deplete the AHR in a time- and dose-dependent manner. In contrast, benzimidazoles are unable to induce CYP1A1 mRNA in mouse hepa-1 cells and to deplete the high-affinity AHR form from these cells. Taken together these data suggest that a signal transduction pathway, similar to that involved in the ligand-independent activation of steroid receptors, could only activate the low-affinity forms of AHR as those existing in rabbit and human cells.
苯并咪唑衍生物是兔和人肝细胞中CYP1A1的有效诱导剂，但显然不与芳烃受体（AH受体）结合。为了解决这种矛盾行为，研究关注的问题是，是否有一种替代的不依赖配体的机制可以解释AH受体的激活。通过在培养的兔肝细胞中进行的实验，我们发现苯并咪唑能早期且短暂地与一种未知蛋白质结合。此外，它们能够以时间和剂量依赖的方式消耗芳烃受体。相比之下，苯并咪唑不能在小鼠hepa-1细胞中诱导CYP1A1 mRNA，也不能从这些细胞中消耗高亲和力的芳烃受体形式。综合这些数据表明，类似于参与类固醇受体不依赖配体激活的信号转导途径，可能只能激活兔和人细胞中存在的低亲和力形式的芳烃受体。
