INHIBITION OF KUPFFER CELL FUNCTIONS AS AN EXPLANATION FOR THE HEPATOPROTECTIVE PROPERTIES OF SILIBININ

The flavonoid silibinin, the main compound extracted hom the milk this tle Silybum man'anum, displays hepatoprotective properties in acute an d chronic liver injury. To further elucidate the mechanisms by which i t acts, we studied the effects of silibinin on different functions of isolated rat Kupffer cells, namely the formation of superoxide anion r adical (O-2(-)), nitric oxide (NO), tumor necrosis factor alpha (TNF-a lpha), prostaglandin E(2) (PGE(2)), and leukotriene B-4 (LTB(4)). Prod uction of O-2(-) and NO were inhibited in a dose-dependent manner, wit h an 50% inhibitory concentration (IC50) value around 80 mu mol/L. No effect on TNF-alpha formation was detected. Opposite effects were foun d on the cyclooxygenase and 5-lipoxygenase pathway of arachidonic acid metabolism, Whereas no influence on PGE(2) formation was observed wit h silibinin concentrations up to 100 mu mol/L, a strong inhibitory eff ect on LTB(4) formation became evident. The IC50-value for inhibiting the formation of this eicosanoid was determined to be 15 mu mol/L sili binin. The strong inhibition of LTB(4) formation by silibinin was conf irmed 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, significan t inhibition of the B-lipoxygenase pathway already occurs at silibinin concentrations which are achieved in vivo. Selective inhibition of le ukotriene formation by Kupffer cells can at least partly account for t he hepatoprotective properties of silibinin.