Induction of CYP1A by the N-imidazole derivative, 1-benzylimidazole.
Xenobiotics can induce cytochrome P4501A (CYP1A) by ligand binding to the aryl hydrocarbon receptor (AhR). Typical AhR ligands are polycyclic aromatic compounds with planar molecular conformation. The present work investigated the ability of the N-imidazole derivative, 1-benzylimidazole (BIM), to induce CYP1A in rainbow trout hepatocytes. Benzylimidazole increased hepatocellular CYP1A catalytic activity (determined as 7-ethoxyresorufin-O-deethylase [EROD] activity) and CYP1A mRNA in a concentration-dependent way. Computational studies on the molecular structure of BIM indicated that the energetically most stable BIM conformer has the imidazole ring and the phenyl ring in different planes, i.e., does not take a planar conformation. This property of BIM does not agree with the structural requirements of a typical AhR ligand. In line with this observation, we found that the AhR antagonist, alpha-naphthoflavone (alphaNF), was not able to inhibit BIM induction of EROD activity and CYP1A mRNA, although it inhibited the induction of CYP1A by the prototypic AhR ligand, beta-naphthoflavone (betaNF). The results suggest that transcriptional activation of CYP1A by the N-imidazole derivative, BIM, is not mediated through direct ligand binding to the AhR.
Navas
José María
JM
Department of Chemical Ecotoxicology, UFZ Centre for Environmental Research, Permoserstrasse 15, D-04318 Leipzig, Germany.
Chana
Antonio
A
Herradón
Bernardo
B
Segner
Helmut
H
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014337:Trout; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001571:Benzoflavones; D007093:Imidazoles; D012333:RNA, Messenger; C017062:1-benzylimidazole; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; D019363:Cytochrome P-450 CYP1A1