Dapsone impairs the bile salt-independent fraction of bile flow in rats: Possible involvement of its N-hydroxylated metabolite

The effects of dapsone (DDS) treatment (30 mg/kg body wt, twice a day, for 4 days) on biliary secretory function, with special emphasis on bile salt independent bile flow (BSIF), were investigated in male and in female Wistar rats. Because DDS is metabolized to its N-hydroxylated parent compound only in male rats, any gender difference in DDS effect can be causally attributed to this metabolite. The two main driving forces for BSIF, the biliary secretion of HCO3− and glutathione species, were assessed. BSIF was decreased by about 20% in male but not in female rats after DDS treatment. Basal biliary HCO3− secretion was decreased also by 20% in males. This was associated with a diminished (−37%) expression of the HCO3− canalicular transporter, anion exchanger 2 (AE2), detected by western blotting. Biliary output of reduced glutathione (GSH) was not modified by DDS irrespective of gender, whereas excretion of oxidized glutathione (GSSG) was increased by 830% in males. This latter finding confirmed a gender-dependent oxidative stress associated with formation of the N-hydroxylated metabolite of DDS. The expression of multidrug resistance-associated protein 2 (Mrp2), a putative transporter of glutathione species, was decreased by 38% as detected by western blotting, clearly dissociating from preserved or increased biliary excretion of GSH and GSSG. In conclusion, our results show an impairment of BSIF by DDS mainly due to a decreased AE2-mediated biliary excretion of HCO3−, formation of the N-hydroxylated metabolite of DDS being a likely mediator. The clinical relevance of these findings is discussed.