Modulation of paracetamol metabolism by Kupffer cells: a study on rat liver slices

Recent studies support the hypothesis that non parenchymal cells (mainly macrophages) may play a role in the metabolism and cellular effects of paracetamol. In order to investigate this hypothesis, male Wistar rats were intravenously injected with either 7.5 mg/kg gadolinium chloride (Gd+) or NaCl 0.9% (Gd-). The treatment with GdCl3 decreased the number and the function of Kupffer cells in liver tissue, as assessed by the histological examination of the liver after colloidal carbon injection in the portal vein. Precision-cut liver slices (PCLS) were prepared from both groups of rats and cultured for 8h in Waymouth's medium in the presence and absence of 5 mM paracetamol. Interestingly, PCLS obtained from Gd+ rats exhibited a lower release of tumor necrosis factor (TNF-alpha) and a better viability than PCLS from control (Gd-) rats. Incubation with paracetamol led to a decreased glycogen level in liver slices from Gd+ or Gd-, without modifying neither liver morphology nor ATP level nor LDH release. A higher proportion of paracetamol glucuronide, was secreted from the slices obtained from Gd+ rats. These data suggest that Kupffer cells could affect the viability of PCLS in culture and are involved in the regulation of phase II metabolism in the adjacent hepatocytes. We propose that PCLS in culture is a suitable model to elucidate the biochemical mechanism underlying the modulation of metabolism occurring through hepatocytes-Kupffer cells interactions.