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Longevity"],"published-print":{"date-parts":[[2019,2,12]]},"abstract":"<jats:p>Bilirubin is considered to be one of the most potent endogenous antioxidants in humans. Its serum concentrations are predominantly affected by the activity of hepatic bilirubin UDP-glucuronosyl transferase (UGT1A1). Our objective was to analyze the potential bilirubin-modulating effects of natural polyphenols from milk thistle (<jats:italic>Silybum marianum<\/jats:italic>), a hepatoprotective herb. Human hepatoblastoma HepG2 cells were exposed to major polyphenolic compounds isolated from milk thistle. Based on <jats:italic>in vitro<\/jats:italic> studies, 2,3-dehydrosilybins A and B were selected as the most efficient compounds and applied either intraperitoneally or orally for seven days to C57BL\/6 mice. After, <jats:italic>UGT1A1<\/jats:italic> mRNA expression, serum, intrahepatic bilirubin concentrations, and lipoperoxidation in the liver tissue were analyzed. All natural polyphenols used increased intracellular concentration of bilirubin in HepG2 cells to a similar extent as atazanavir, a known bilirubinemia-enhancing agent. Intraperitoneal application of 2,3-dehydrosilybins A and B (the most efficient flavonoids from <jats:italic>in vitro<\/jats:italic> studies) to mice (50\u2009mg\/kg) led to a significant downregulation of <jats:italic>UGT1A1<\/jats:italic> mRNA expression (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\"><mml:mn>46<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>3<\/mml:mn><mml:mo>%<\/mml:mo><\/mml:math> of controls, <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\"><mml:mi>p<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.005<\/mml:mn><\/mml:math>) in the liver and also to a significant increase of the intracellular bilirubin concentration (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M3\"><mml:mn>0.98<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>0.03<\/mml:mn><\/mml:math><jats:italic>vs.<\/jats:italic><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M4\"><mml:mn>1.21<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>0.02<\/mml:mn><mml:mtext>\u2009<\/mml:mtext><mml:mtext>nmol<\/mml:mtext><mml:mo>\/<\/mml:mo><mml:mtext>mg<\/mml:mtext><\/mml:math>, <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M5\"><mml:mi>p<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.05<\/mml:mn><\/mml:math>). Simultaneously, a significant decrease of lipoperoxidation (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M6\"><mml:mn>61<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>2<\/mml:mn><mml:mo>%<\/mml:mo><\/mml:math> of controls, <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M7\"><mml:mi>p<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.005<\/mml:mn><\/mml:math>) was detected in the liver tissue of treated animals, and similar results were also observed after oral treatment. Importantly, both application routes also led to a significant elevation of serum bilirubin concentrations (<mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M8\"><mml:mn>125<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>3<\/mml:mn><mml:mo>%<\/mml:mo><\/mml:math> and <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M9\"><mml:mn>160<\/mml:mn><mml:mo>\u00b1<\/mml:mo><mml:mn>22<\/mml:mn><mml:mo>%<\/mml:mo><\/mml:math> of the controls after intraperitoneal and oral administration, respectively, <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M10\"><mml:mi>p<\/mml:mi><mml:mo>&lt;<\/mml:mo><mml:mn>0.005<\/mml:mn><\/mml:math> in both cases). In conclusion, polyphenolic compounds contained in silymarin, in particular 2,3-dehydrosilybins A and B, affect hepatic and serum bilirubin concentrations, as well as lipoperoxidation in the liver. This phenomenon might contribute to the hepatoprotective effects of silymarin.<\/jats:p>","DOI":"10.1155\/2019\/6026902","type":"journal-article","created":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T18:40:26Z","timestamp":1549996826000},"page":"1-12","source":"Crossref","is-referenced-by-count":23,"title":["Isolated Silymarin Flavonoids Increase Systemic and Hepatic Bilirubin Concentrations and Lower Lipoperoxidation in Mice"],"prefix":"10.1155","volume":"2019","author":[{"given":"Jakub","family":"\u0160uk","sequence":"first","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Kate\u0159insk\u00e1 32, Praha 2 12000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Ja\u0161prov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, 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V\u00edde\u0148sk\u00e1 1082, Praha 4 14000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1091-4020","authenticated-orcid":true,"given":"Vladim\u00edr","family":"K\u0159en","sequence":"additional","affiliation":[{"name":"Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, V\u00edde\u0148sk\u00e1 1082, Praha 4 14000, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-1060","authenticated-orcid":true,"given":"Lucie","family":"Muchov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Kate\u0159insk\u00e1 32, Praha 2 12000, Czech 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