INFLUENCE OF SUBCHRONIC ADMINISTRATION OF ESTRADIOL, ETHINYLESTRADIOLAND ESTRADIOL SULFAMATE ON BILE-FLOW, BILE-ACID EXCRETION, AND LIVER AND BILIARY GLUTATHIONE STATUS IN RATS

The cholestatic effect of the newly developed oestradiol sulphamate (J 995) was compared with that of the natural oestrogen oestradiol (E) an d of the cholestatic standard oestrogen ethinyloestradiol (EE). Female ovariectomized rats were orally treated for 7 days with oestrogen dos es 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 glutath ione status were determined after bile duct cannulation under the infl uence of ketamine anaesthesia. For systemic oestrogen activity, the in crease of uterine weight was measured. J995 showed the highest oestrog enic activity followed by EE and E. Impairment of bile flow and biliar y glutathione excretion (GSH, GSSG) were found to be in the order E < J995 < EE. As all three oestrogens did not influence bile acid excreti on, we postulate that mainly the bile acid-independent fraction of bil e flow was inhibited, caused at least partly by impairment of canalicu lar glutathione transport. Based on the results of these studies, we c onclude that a tenfold higher dose of J995 exhibited the same cholesta tic effect as EE. Together with higher systemic oestrogenic activity, J995 may be used as a prodrug with reduced hepatic side-effects to rep lace EE in contraception strategies.