EVIDENCE FOR THE LIGAND-INDEPENDENT ACTIVATION OF THE AH RECEPTOR

Benzimidazole derivatives are potent inducers of CYP1A1 in rabbit and human hepatocytes, but apparently do not bind the AH receptor. To reso lve this paradoxical behaviour, studies have been concerned with the q uestion of whether an alternative ligand-independent mechanism could e xplain the activation of the AH receptor. From experiments in cultured rabbit hepatocytes we show that benzimidazoles bind early and transie ntly 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 su ggest that a signal transduction pathway, similar to that involved in the ligand-independent activation of steroid receptors, could only act ivate the low-affinity forms of AHR as those existing in rabbit and hu man cells. (C) 1995 Academic Press. Inc.