INDUCTION OF CYP1A BY VARIOUS BENZIMIDAZOLES AND ITS SIGNIFICANCE IN ADMINISTRATIVE DRUG REGULATION

The introduction of benzimidazole derivatives as selective H super(+)/K super(+)-ATPase enzyme inhibitors, including omeprazole (OM), lansoprazole (LAN), and pantoprazole (PAN), has led to a new therapeutic mode for gastric and duodenal ulcer disease with the eradication of Helicobacter pylori as the causative agent. However, in rare cases, severe side effects of complicated vision disturbances [anterial ischemic opticus neuropathy (AION)] occurred in individual patients, who received higher doses of omeprazole (documented in the pharmacovigilance database of the BfArM), or--under a clinical precarious situation--by intravenous route. The BfArM was forced to take moderate measures for reducing the risks and optimizing the necessary effective dosage of proton pump inhibitors. Because of the strong inducing potency of benzimidazoles on P450 1A forms, a rather indirect hypothesis of pathogenesis appeared to be probable {e.g., a drastic increase of CYP1A content in the target tissue can result in a critical change of the endogenous arachidonic acid metabolite pattern in favor of vasoactive hydroperoxy forms [12(R)-HETE]}. The CYP1A forms are induced by the activation of the arylhydrocarbon receptor (AHR). Inducers like OM might also activate other AHR-driven genes like CYP1B1, which has a substrate specificity similar to CYP1A1. Consequently, the induction behavior of three different established cell lines (HepG2, HUH7, HELA) was investigated following incubation with five benzimidazoles [OM, LAN, PAN, E3810, and mebendazole (MEB,)] and the novel angiotensin II receptor antagonist Losartan (LOS,). Additionally, the induction of CYP1B1 by OM in man was investigated in a clinical trial. Transcription is known as a limiting step in the sequence of molecular events during protein biosynthesis stimulated by 3-methylcholanthrene (3-MC) treatment. Protein kinases, DNA-dependent RNA polymerases, nuclear receptor proteins, and especially certain transcription factors play a key role in the individual disposition of metabolic toxifying and detoxifying processes.