title: Blockage of multidrug resistance-associated proteins potentiates the inhibitory effects of arsenic trioxide on CYP1A1 induction by polycyclic aromatic hydrocarbons.
abstract: Arsenic is a toxic metalloid known to interact with drug-metabolizing enzymes. In the present study, we investigated the effects of arsenic trioxide (As2O3), recently used as an anticancer drug, on the expression of human cytochrome P450 (P450) 1A1, which bioactivates polycyclic aromatic hydrocarbons into mutagenic metabolites. Clinically relevant concentrations (0.25-5 microM) of As2O3 were demonstrated to inhibit CYP1A activity in primary human hepatocytes and hepatoma Hep3B and HepG2 cells coexposed to 3-methylcholanthrene (3MC), benzo(a)pyrene, or dioxin and the metalloid for 24 h. Inhibition reached 50 and 90% in Hep3B cells treated with 1 and 5 microM As2O3, respectively, and was not due to direct interaction of the metalloid with CYP1A1. As2O3 (2.5-5 microM) was demonstrated to markedly reduce induction of CYP1A1 mRNA and apoprotein levels and gene promotor activity in 3MC-treated Hep3B cells, whereas lower concentrations (0.25-1 microM) were ineffective. These effects of As2O3 were abrogated by N-acetylcysteine. Surprisingly, this agent was found 1) to block cellular arsenic uptake when coincubated with the metalloid and 2) to increase arsenic efflux through multidrug resistance-associated proteins. In addition, blockade of these transporters was shown to enhance intracellular amounts of metalloid and to potentiate its effects on CYP1A1 gene. Finally, our results have demonstrated that As2O3, at low concentrations routinely reached in As2O3-treated patients, prevents induction of human CYP1A1 gene expression and that such an effect is increased by blocking multidrug resistance-associated proteins.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U456, Détoxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes I, Rennes, France. laurent.vernhet@rennes.inserm.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernhet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Allain
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vée
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morel
authors.forename: André
authors.initials: A
authors.lastname: Guillouzo
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000378:metabolism; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis; D010087:Oxides / Q000494:pharmacology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D004147:Dioxins; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010087:Oxides; D011084:Polycyclic Aromatic Hydrocarbons; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C093947:MRP2 protein, S cerevisiae; C421109:multidrug resistance-associated protein 1