Modulation by S-Adenosyl-L-Methionine of Hepatic Na+, K+-ATPase, Membrane Fluidity, and Bile Flow in Rats with Ethinyl Estradiol-Induced Cholestasis

Abstract

Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug-induced cholestasis. To elucidate the mechanism by which S-adenosyl-L-methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague-Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (26 mg per kg, 3 times per day, for 3 days). Na',K'-ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE-treated rats resulted in a marked increase in Na+,K+-ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic M&+-ATPase and y-glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in viuo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+,K+-ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+,K'-ATPase was associated with SAMe-induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE-induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE-induced impairment of bile secretory function.

Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs?

“…They observed that EE treatment significantly reduced the activity of Na + , K + -ATPase, accompanied by the diminishment of bile flow, and that canalicular Na + , K + -ATPase activity was significantly correlated with bile flow. These observations were confirmed by several subsequent studies [130][131][132], supporting an important role of Na + , K + -ATPase activity in the regulation of bile flow by EE [130][131][132][133]. In contrast to EE, E2 was found to stimulate Na + , K + -ATPase activity.…”

“…17b-estradiol (E2) and estrogen-like molecules, could be ligands of Na + , K + -ATPase. It has been known that the synthetic estrogen, ethinyl estradiol (EE), induced impairment of bile flow and bile salt maximum secretory function in rat liver and that the structural and functional changes in surface membranes of hepatocytes play a pivotal role in EE-induced cholestasis [130][131][132]. Reichen and Paumgartner [133] studied the relationship between bile flow and Na + , K + -ATPase in liver plasma membranes enriched in canaliculi in rats treated with EE.…”

Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters

“…In some forms of liver diseases, the activity of (Na + , K + )-ATPase may be impaired as shown in an animal model of endotoxin-induced cholestasis (156). Also, treatment of rats with pharmacologic doses of ethinylestradiol has been found by some to reduce the activity of (Na + , K + )-ATPase (11,107) but not by others (17,18,95) 2. NTCP expression can be up or down regulated in certain forms of human liver diseases.…”

Cholestasis of Pregnancy

“…By altering function at the level of the hepatic surface membrane, SAMe improves the impairment of bile flow caused by increased levels of ethinyl estradiol. 69 Studies of SAMe in rats have shown reversal of cholestasis in those treated with ethinyl estradiol. 70 Several randomized studies examining SAMe have been performed in humans with ICP.…”