Aim: Genipin is reported to stimulate the insertion of multidrug resistance protein 2 (Mrp2) in the bile canalicular membrane, thereby causing choleresis by the increased the biliary excretion of glutathione, which has been considered to be a substrate of Mrp2. In the present study, we examined the effect of genipin on cholestasis induced by estradiol-17beta-glucuronide and lithocholate-3-O-glucuronide, Mrp2 substrates, in rats. Further, the effect of genipin on the biliary excretion of substrates of P-glycoprotein (P-gp), vinblastine and erythromycin, was also studied.
Methods: The effect of genipin infusion at the rate of 0.5 micromol/min/100 g on cholestasis induced by estradiol-17beta-glucuronide (0.075 micromol/min/100 g for 20 min) and lithocholate-3-O-glucuronide (0.15 micromol/min/100 g for 40 min) was studied. The effect of genipin infusion on the biliary excretion of a tracer dose of vinblastine and erythromycin infused at the rate of 0.1 micromol/min/100 g was also studied.
Results: Genipin relieved estradiol-17beta-glucuronide-induced cholestasis, and cumulative biliary estradiol-17beta-glucuronide excretion for 120 min was increased from 50 +/- 20%-81 +/- 20% dose. In contrast, genipin had no effect on lithocholate-3-O-glucuronide-induced cholestasis. Biliary excretion of a tracer dose of vinblastine and the maximum biliary excretion of erythromycin were significantly decreased by genipin.
Conclusions: Genipin protected estradiol-17beta-glucuronide-induced cholestasis. The mechanism of the protection of cholestasis by genipin is unknown, but it is speculated to be due to a conformational change of P-gp by genipin, in addition to the stimulation of Mrp2 insertion into the bile canaliculi.