Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin

Abstract

The flavonoid silibinin, the main compound extracted from the milk thistle Silybum marianum, displays hepatoprotective properties in acute and chronic liver injury. To further elucidate the mechanisms by which it acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion radical (0 2 −), nitric oxide (NO), tumor necrosis factor α (TNF- α), prostaglandin E 2 (PGE 2), and leukotriene B 4 (LTB 4). Production of 0 2 − and NO were inhibited in a dose-dependent manner, with an 50% inhibitory concentration (IC 50) value around 80 μmol/L. No effect on TNF-α formation was detected. Opposite effects were found on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism. Whereas no influence on PGE 2 formation was observed with silibinin concentrations up to 100 μmol/L, a strong inhibitory effect on LTB 4 formation became evident. The IC 50- value for inhibiting the formation of this eicosanoid was determined to be 15 μmol/L silibinin. The strong inhibition of LTB 4, formation by silibinin was confirmed in experiments with phagocytic cells isolated from human liver. Hence, while rather high concentrations of silibinin are necessary to diminish free radical formation by activated Kupffer cells, significant inhibition of the 5-lipoxy-genase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin.