Influence of subchronic administration of oestradiol, ethinyloestradiol and oestradiol sulphamate on bile flow, bile acid excretion, and liver and biliary glutathione status in rats.

The cholestatic effect of the newly developed oestradiol sulphamate (J995) was compared with that of the natural oestrogen oestradiol (E) and of the cholestatic standard oestrogen ethinyloestradiol (EE). Female ovariectomized rats were orally treated for 7 days with oestrogen doses molar equivalent to 0.01, 0.1, 1, and 10 mg E/kg body wt. Bile flow, biliary bile acid and glutathione excretion as well as liver glutathione status were determined after bile duct cannulation under the influence of ketamine anaesthesia. For systemic oestrogen activity, the increase of uterine weight was measured. J995 showed the highest oestrogenic activity followed by EE and E. Impairment of bile flow and biliary glutathione excretion (GSH, GSSG) were found to be in the order E < J995 < EE. As all three oestrogens did not influence bile acid excretion, we postulate that mainly the bile acid-independent fraction of bile flow was inhibited, caused at least partly by impairment of canalicular glutathione transport. Based on the results of these studies, we conclude that a tenfold higher dose of J995 exhibited the same cholestatic effect as EE. Together with higher systemic oestrogenic activity, J995 may be used as a prodrug with reduced hepatic side-effects to replace EE in contraception strategies.