Characterization of the antiallergic drugs 3-[2-(2-phenylethyl) benzoimidazole-4-yl]-3-hydroxypropanoic acid and ethyl 3-hydroxy-3-[2-(2-phenylethyl)benzoimidazol-4-yl]propanoate as full aryl hydrocarbon receptor agonists.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates most of the toxic effects of numerous chlorinated (e.g., TCDD) and nonchlorinated polycyclic aromatic compounds (e.g., benzo[ a]pyrene). Studies in AhR null mice suggested that this receptor may also play a role in the modulation of immune responses. Recently, two drugs, namely, M50354 and M50367 (ethyl ester derivative of M50354), were described as AhR ligands with high efficacy toward reducing atopic allergic symptoms in an AhR-dependent manner by skewing T helper cell differentiation toward a T H1 phenotype [Negishi et al. (2005) J. Immunol. 175 (11), 7348-7356]. Surprisingly, these drugs were shown to have minimal activity toward inducing classical dioxin responsive element-driven AhR-mediated CYP1A1 transcription. We synthesized and reevaluated the ability of these drugs to regulate AhR activity. In contrast to previously published data, both M50354 and M50367 were found to be potent inducers of several AhR target genes, namely, CYP1A1, CYP1B1, and UGT1A2. M50367 was a more effective agonist than M50354, perhaps accounting for its higher bioavailability in vivo. However, M50354 was capable of displacing an AhR-specific radioligand more effectively than M50367. This is consistent with M50354 being the active metabolite of M50367. In conclusion, two selective inhibitors of TH2 differentiation are full AhR agonists.
Morales
José Luis
JL
Graduate Program in Biochemistry, Microbiology, and Molecular Biology, Department of Pharmacology, College of Medicine, The Pennsylvania State University, University Park, PA 16802, USA.
Krzeminski
Jacek
J
Amin
Shantu
S
Perdew
Gary H
GH
D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000187:drug effects* / Q000235:genetics
D018926:Anti-Allergic Agents; D001562:Benzimidazoles; C119626:M 50367; C506997:M50354; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D001189:Aryl Hydrocarbon Hydroxylases