Description:
<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 mg/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>±</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><</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>±</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>±</mml:mo><mml:mn>0.02</mml:mn><mml:mtext> </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><</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>±</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><</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>±</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>±</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><</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>