Menadione Suppresses Benzo(alpha)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

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Sidorova YA, Perepechaeva ML, Pivovarova EN, Markel AL, Lyakhovich VV, Grishanova AY

Menadione Suppresses Benzo(alpha)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

PLoS One. 2016 May 11;11(5):e0155135. doi: 10.1371/journal.pone.0155135. eCollection 2016.

PubMed ID

27167070 [ View in PubMed

]

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(alpha)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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Menadione	Cytochrome P450 1A1	Protein	Humans	Unknown	Inhibitor Inducer	Details
Menadione	Cytochrome P450 1A2	Protein	Humans	Unknown	Inhibitor Inducer	Details