The gene expression profile of a drug metabolism system and signal transduction pathways in the liver of mice treated with tert-butylhydroquinone or 3-(3'-tert-butyl-4'-hydroxyphenyl)propylthiosulfonate of sodium

Autor: Vyacheslav V. Lyakhovich, Valentin A. Vavilin, Olga G. Safronova, Alexandra B. Shintyapina
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Enzyme Metabolism
Thiosulfonic Acids
Retinoic acid
Gene Expression
lcsh:Medicine
Pharmacology
Biochemistry
Antioxidants
Mice
chemistry.chemical_compound
Drug Metabolism
Cytochrome P-450 Enzyme System
Gene expression
Medicine and Health Sciences
Enzyme Chemistry
lcsh:Science
Mice
Inbred BALB C
Multidisciplinary
Chemistry
Wnt signaling pathway
Glutathione
Liver
Physical Sciences
Inactivation
Metabolic
Microsomes
Liver
Metabolic Pathways
Signal transduction
Research Article
Signal Transduction
Blotting
Western
Real-Time Polymerase Chain Reaction
03 medical and health sciences
Phenols
Genetics
Cancer Genetics
Xenobiotic Metabolism
Animals
Pharmacokinetics
Protein kinase B
PI3K/AKT/mTOR pathway
lcsh:R
Chemical Compounds
Biology and Life Sciences
Oncogenes
KEAP1
Hydroquinones
Metabolism
030104 developmental biology
Enzymology
lcsh:Q
Peptides
Transcriptome
Drug metabolism
Zdroj: PLoS ONE, Vol 12, Iss 5, p e0176939 (2017)
PLoS ONE
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0176939
Popis: Tert-butylhydroquinone (tBHQ) is a highly effective phenolic antioxidant used in edible oils and fats in foods as well as in medicines and cosmetics. TBHQ has been shown to have both chemoprotective and carcinogenic effects. Furthermore, it has potential anti-inflammatory, antiatherogenic, and neuroprotective activities. TBHQ induces phase II detoxification enzymes via the Keap1/Nrf2/ARE mechanism, which contributes to its chemopreventive functions. Nonetheless, there is growing evidence that biological effects of tBHQ may be mediated by Nrf2-independent mechanisms related to various signaling cascades. Here, we studied changes in gene expression of phase I, II, and III drug metabolizing enzymes/transporters as well as protein levels and activities of cytochromes P450 (CYPs) elicited by tBHQ and its structural homolog TS-13 in the mouse liver. Next, we carried out gene expression analysis to identify signal transduction pathways modulated by the antioxidants. Mice received 100 mg/kg tBHQ or TS-13 per day or only vehicle. The liver was collected at 12 hours and after 7 days of the treatment. Protein and total RNA were extracted. Gene expression was analyzed using Mouse Drug Metabolism and Signal Transduction PathwayFinder RT2Profiler™PCR Arrays. A western blot analysis was used to measure protein levels and a fluorometric assay was employed to study activities of CYPs. Genes that were affected more than 1.5-fold by tBHQ or TS-13 treatment compared with vehicle were identified. Analysis of the gene expression data revealed changes in various genes that are important for drug metabolism, cellular defense mechanisms, inflammation, apoptosis, and cell cycle regulation. Novel target genes were identified, including xenobiotic metabolism genes encoding CYPs, phase II/III drug metabolizing enzymes/transporters. For Cyp1a2 and Cyp2b, we observed an increase in protein levels and activities during tBHQ or TS-13 treatment. Changes were found in the gene expression regulated by NFκB, androgen, retinoic acid, PI3K/AKT, Wnt, Hedgehog and other pathways.
Databáze: OpenAIRE
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