Reversal of ethinyl estradiol-induced bile secretory failure with Triton WR-1339.
The effects of Triton WR-1339 and phenobarbital on ethinyl estradiol bile secretory failure were examined to determine the mechanism responsible for decreased bile salt excretion. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored bile salt independent bile flow and maximum taurocholate transport, whereas phenobarbital corrected bile flow only. Ethinyl estradiol decreased the activities of Na(+)-K(+)-ATPase, 5'-nucleotidase, while increasing the activities of Mg(++)-ATPase and alkaline phosphatase. In contrast to these heterogeneous changes in surface membrane enzyme activities, the number and affinity of [(14)C]cholic acid carriers were not altered. When administered in vivo or added directly to surface membrane fractions Triton WR-1339 restored the activities of Na(+)-K(+)-ATPase and Mg(++)-ATPase of rats treated with ethinyl estradiol through a process that did not require protein synthesis (unaffected by cycloheximide). Phenobarbital also restored the activity of Na(+)-K(+)-ATPase to control levels, but, unlike Triton WR-1339 it did not correct the defect responsible for reduced bile salt secretion. Ethinyl estradiol increased the concentration of cholesterol esters in surface membrane fractions. When administered to ethinyl estradiol-treated rats, Triton WR-1339 restored cholesterol ester concentrations to normal, whereas phenobarbital did not. These combined data suggest that decreased or altered bile salt carriers or reduced sodium driving forces resulting from impaired activity of Na(+)-K(+)-ATPase are not responsible for decreased bile salt excretion in ethinyl estradiol-treated rats. It is proposed that the diverse changes in surface membrane function, which are associated with ethinyl estradiol bile secretory failure, may be the result of a generalized alteration in membrane lipid structure.
D000818:Animals; D001646:Bile / Q000187:drug effects* / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D001647:Bile Acids and Salts; D008563:Membrane Lipids; D011092:Polyethylene Glycols; D004997:Ethinyl Estradiol; D003513:Cycloheximide; D000254:Sodium-Potassium-Exchanging ATPase; C016811:tyloxapol; D010634:Phenobarbital