title: Menadione Suppresses Benzo(α)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.
abstract: Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A) lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs), such as the widespread environmental pollutant benzo(α)pyrene (BP). These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR)-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3) inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver) and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP), which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR)-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.
authors.affiliation: Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Sidorova
authors.affiliation: Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Perepechaeva
authors.affiliation: Federal research center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Pivovarova
authors.affiliation: Federal research center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.
authors.forename: Arkady L
authors.initials: AL
authors.lastname: Markel
authors.affiliation: Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.
authors.forename: Vyacheslav V
authors.initials: VV
authors.lastname: Lyakhovich
authors.affiliation: Institute of Molecular Biology and Biophysics, Novosibirsk, Russia.
authors.forename: Alevtina Y
authors.initials: AY
authors.lastname: Grishanova
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D024483:Vitamin K 3 / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: C497398:ARNT protein, rat; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D024483:Vitamin K 3; D004247:DNA; D019363:Cytochrome P-450 CYP1A1