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Isolation of a nuclear receptor in the steroid-thyroid hormone-retinoid orphan receptor superfamily for steroid xenobiotic response elements has led to the isolation of a Xenopus laevis homolog (XlAHR) or a human homolog (hAHR). Using a heterologous expression system we have characterized both the constitutive and ligand-induced function of this receptor. Activation of the receptor by agonists and by metabolic activation of the ligand resulted in nuclear localization of the receptor and binding to the XlAHR response element. This response was completely inhibited by the glucocorticoid receptor antagonist RU 486, indicating that the response element and the receptor possess a glucocorticoid response element. Measurement of the ligand binding affinity of the receptor showed no difference for the interaction of the xenobiotic ligands with either the AHR or the glucocorticoid receptors. Receptor activation of the AHR-responsive element was accompanied by induction of a luciferase gene construct containing 12 half-sites of the response element. This induction was blocked by co-expression of the receptor-antagonist RU 486. In the presence of the AHR ligand 3-MC the receptor-antagonist interaction did not block the ligand-dependent induction of the luciferase reporter gene. Our data suggest that the AHR alone does not confer response to these xenobiotic ligands. The results indicate that the AHR activation in heterologous expression systems may be mediated by a mechanism different from the mechanism that governs the endocrine induction of similar promoters. The inhibitory effects of the AHR-antagonist RU 486 on ligand-induced
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