Effect of tauroursodeoxycholate and S-adenosyl- -methionine on 17β-estradiol glucuronide-induced cholestasis

Background/Aims: S-adenosyl- -methionine (SAMe) and tauroursodeoxycholate (TUDC) exert an additive ameliorating effect on taurolithocholate (TLC)-induced cholestasis. The aims were to investigate the protective effect of SAMe on 17beta-estradiol-glucuronide (17βEG) cholestasis and to find out whether SAMe and TUDC may exert an additive, ameliorating effect. Methods: Hepatocyte couplet function was assessed by canalicular vacuolar accumulation (cVA) of cholyllysylfluorescein (CLF). Cells were co-treated with 17βEG and SAMe, TUDC, or both (protection study), or treated with 17βEG and then with SAMe, TUDC or both (reversion study) before CLF uptake. Couplets were also co-treated with SAMe and dehydroepiandrosterone (DHEA), a competitive substrate for the sulfotransferase involved in 17βEG detoxification. The effects of 17βEG, SAMe and TUDC were also examined on intracellular distribution of F-actin. Results: Both SAMe and TUDC significantly protected against, and reversed, 17βEG-induced cholestasis, but their effects were not additive. DHEA abolished the protective effect of SAMe. 17βEG did not affect the uptake of CLF into hepatocytes at the concentrations used, and also, it did not affect the intracellular distribution of F-actin. Conclusions: 17βEG does not affect the uptake of CLF into hepatocytes. SAMe and TUDC protect and reverse 17βEG-induced cholestasis, but without an additive effect. Protection by SAMe may involve facilitating the sulfation of 17βEG.