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Cholestasis Induced by Estradiol‐17β‐D‐Glucuronide: Mechanisms and Prevention by Sodium Taurocholate
Author(s) -
Adinolfi Luigi E.,
Utili Riccardo,
Gaeta Giovanni B.,
Abernathy Charles O.,
Zimmerman Hyman J.
Publication year - 1984
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.1840040106
Subject(s) - cholestasis , glucuronide , taurocholic acid , sodium , medicine , chemistry , endocrinology , pharmacology , bile acid , metabolism , organic chemistry
Estradiol‐17β‐D‐glucuronide (E‐17G), a metabolite of natural estrogen, is a potent cholestatic agent in vivo. We, therefore, studied the mechanisms of E‐17G cholestasis using in vitro perfused rat liver system. Furthermore, since it has been postulated that sodium taurocholate (TC) may interfere with either uptake or biliary excretion of other steroid agents, we tested whether E‐17G cholestasis could be modified by TC administration. During a constant infusion of TC at a physiological rate (0.50 μ mole per min), a dose‐dependent decrease of bile flow was observed after E‐17G addition from 1.5 to 5 x 10 −5 M . E‐17G decreased bile acid excretory rate but not bile acid concentration in bile. In separate experiments, TC was infused at different rates (0, 0.25, 0.50, and 0.75 μ mole per min) into the perfusate over the entire experimental period, and E‐17G was added at 1.75 x 10 −5 M . In this setting, E‐17G cholestasis was diminished by increasing TC infusion rate and was prevented by TC at 0.75 μ mole per min. Infusion of sodium dehydrocholate (0.75 μ mole per min), a nonmicelle‐forming bile acid, did not prevent E‐17G cholestasis. During E‐17G cholestasis, an increased biliary permeability to 14 C‐sucrose was observed. This effect was also prevented by TC, but not by sodium dehydrocholate which was infused at 0.75 μ mole per min. The perfusate disappearance curves of 3 H‐E‐17G at the different TC infusion rates showed no changes in the initial uptake phase, but a profound dose‐dependent difference in the excretory phase. The amount of E‐17G left in perfusate at the end of experiments was 34% when no TC was infused and decreased to 28%; 22 and 7% at 0.25; 0.50 and 0.75 nmole per min TC rate, respectively. Measurement of 3 H‐E‐17G excreted in bile as well as its biliary concentration in the four TC groups showed that TC significantly increased E‐17G excretion. Small amounts of E‐17G were recovered in liver plasma membranes. However, these amounts were directly proportional to changes of bile flow induced by estrogen at different TC infusion rates. In these same liver membrane preparations, neither Na + ,K + − nor Mg ++ −ATPases were altered. The data suggest that alterations of canalicular membrane permeability may be critical in the development of E‐17G cholestasis. Prevention of E‐17G cholestasis by TC infusion may occur through increased micellar solubilization and facilitated biliary excretion of the estrogen thus avoiding its membrane‐altering action.