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Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver

J. Dusek, J. Skoda, O. Holas, A. Horvatova, T. Smutny, L. Linhartova, P. Hirsova, O. Kucera, S. Micuda, A. Braeuning, P. Pavek,

. 2019 ; 313 (-) : 1-10. [pub] 20190604

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc19034516

The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

Citace poskytuje Crossref.org

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$a Skoda, Josef $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
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$a Holas, Ondrej $u Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
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$a Horvatova, Alzbeta $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
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$a Hirsova, Petra $u Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
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$a Kucera, Otto $u Department of Physiology, Charles University, Faculty of Medicine in Hradec Kralove, Simkova 870, 500 03 Hradec Kralove, Czech Republic.
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$a Pavek, Petr $u Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic. Electronic address: pavek@faf.cuni.cz.
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