Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis.
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 (25 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 Mg2+-ATPase and gamma-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 vivo 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.
D000818:Animals; D001646:Bile / Q000187:drug effects*; D002462:Cell Membrane / Q000201:enzymology; D002779:Cholestasis / Q000139:chemically induced / Q000503:physiopathology*; D004997:Ethinyl Estradiol / Q000009:adverse effects*; D005260:Female; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D008560:Membrane Fluidity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D004997:Ethinyl Estradiol; D012436:S-Adenosylmethionine; D000254:Sodium-Potassium-Exchanging ATPase