Ethinyl Estradiol-induced Cholestasis Research Articles

Effects of bile salt supplementation on biliary secretion in estrogen-treated rats

The aim of the present study was to determine whether bile acid feeding to rats can reverse ethinyl estradiol-induced cholestasis. Animals received ethinyl estradiol (2 mg/kg/day) for 6 days or were coinfused with estrogen plus various bile acids (60 mg/kg/day). Cholestasis could be significantly prevented by tauroursodeoxycholic acid, was partly corrected by ursodeoxycholic acid, and was unchanged by chenodeoxycholic acid. Total bile salt secretion was increased in every group. The secretion of the major primary bile acids (cholic acid and β-muricholic acid) was restored to a large extent in rats supplemented with tauroursodeoxycholate but not in chenodeoxycholate-fed rats. In the former group, the canalicular transport of taurocholate and the bile salt pool size were identical with those of control rats. The hydrophilic-hydrophobic balance of the administered bile salt species appears to be an essential factor in the restoration of bile secretion, the more hydrophilic bile salt having the more hepatoprotective effect.

Effects of iron overload on bile secretion and hepatic porphyrin metabolism in ethinyl extradiol-treated rats

We investigated the effects of ethinyl estradiol (5 mg/kg body wt daily for 5 days, orally) and/or iron sorbitol (50 mg/kg body wt daily for 5 days, i.m.) on bile flow, bile salt independent fraction (BSIF), hepatic ∂-amino-levulinate synthase (ALA-S) and uroporphyrinogen decarboxylase (URO-D) in female rats. Ethinyl estradiol administration was associated with a significant decrease of bile flow and BSIF and an increase in URO-D activity in comparison to control values. Iron alone did not modify biliary parameters, but significantly increased the activity of ALA-S. Combined treatment with ethinyl extradiol plus iron partially corrected the reduction of BSIF and restored the activity of ALA-S and URO-D to control levels. Thus iron appears to exert a partially protective effect against ethinyl estradiol-induced cholestasis. No porphyrinogenic effect was observed.

Biliary permeability during ethinyl estradiol-induced cholestasis studied by segmented retrograde intrabiliary injections in rats

The influence of ethinyl estradiol (EE) treatment on the permeability of the biliary tree in rats has been assessed by the segmented retrograde intrabiliary injection (SRII) technique. Three pairs of compounds were studied, inert [14C]sucrose and [3H]inulin; [14C]taurocholic acid (TC) and [14C]glycocholic acid (GC) and the non-ionic bile acid derivatives [125I]cholyldiglycylhistamine (CG2H) and [131I]cholyltetraglycylhistamine (CG4H). In control rats recovery in bile after SRII was always greater for the larger of any pair of compounds, confirming that the biliary tree acts as a filter, and that decreased recovery from bile during this technique is an index of greater biliary permeability. After EE treatment recovery of all compounds was significantly reduced, thus confirming that EE increases biliary permeability. Recovery of sucrose and inulin fell from 55-65% of the administered dose in controls to 8-9% in EE rats. Recoveries of TC, GC, CG2H and CG4H was also reduced, but their biliary recovery profiles were consistent with marked re-excretion into bile of that portion which had initially passed out of the biliary system by filtration. During the later phase of the experiment excretion of the negatively charged bile acids TC and GC was greater than that of the non-ionic bile acid derivatives CG2H and CG4H. Although the site at which these permeability changes have occurred is unknown, our results are compatible with previous data implicating increased tight junction permeability as a mechanism of EE-induced cholestasis.(ABSTRACT TRUNCATED AT 250 WORDS)

No increase of biliary permeability in ethinylestradiol-treated rats

Ethinylestradiol, administered to male Wistar rats for 5 days (5 mg/kg · day), decreased bile flow in anesthetized animals and in isolated perfused livers. The bile salt secretion rate was diminished. The bile-to-perfusate ratios of [14C]sucrose and [14C]inulin increased significantly, but this could be attributed to the decline of bile flow as indicated by almost identical clearance rates. Theorectical analysis according to Forker and Wheeler yielded diffusion permeability coefficients (K) for sucrose and inulin of 0.243 and 0.037 in controls and 0.273 and 0.038 in ethinylestradiol-treated rats. In contrast, 9 h of α-naphthylisothiocyanate treatment (250 mg/kg) caused cholestasis with heavily decreased bile salt secretion rates. Here, K-values calculated for sucrose and inulin were 0.807 and 0.175. These findings suggest that altered permeability of the paracellular pathway is the cause for α-naphthylisothiocyanate-induced cholestasis, but not the primary event in ethinylestradiol-induced cholestasis.

A-11. 肝内性胆汁うっ滞における肝細胞膜酵素活性および脂質組成の変動

A-11. 肝内性胆汁うっ滞における肝細胞膜酵素活性および脂質組成の変動

Morphology of Liver Cell Tight Junctions in Ethinyl Estradiol Induced Cholestasis

Using freeze-fracture techniques the junctional complex of the hepatocytes in female rats is studied after ethinyl estradiol induced cholestasis. The gap junctions are not changed in this situation in contrast to the altered pattern found in extrahepatic bile duct obstruction. The more or less parallel tight junctional strands around the canalicular lumen are converted into a irregular loose network after estradiol treatment in a similar way as in extrahepatic cholestasis. These modifications in the geometrical arrangement of the strands suggest an increase permeability through the tight junctions so that a backward diffusion of biliary components through intercellular escape is possible.

Spontaneous reversal of ethinyl estradiol-induced cholestasis in the rat.

The spontaneous reversal ethinyl estradiol-induced cholestasis has been documented 7 days after the last estrogen administration in the rat. This finding supports the hypothesis that estrogens produce only a transient functional failure of the hepatocytic structures responsible for bile secretion.

Increased Sulfation and Decreased 7α-Hydroxylation of Deoxycholic Acid in Ethinyl Estradiol-Induced Cholestasis in Rats

Deoxycholic acid conjugation, transport capacity, and metabolism were compared in control and ethinyl estradiol-treated rats. Control rats were found to have a lower capacity to transport deoxycholic acid than taurodeoxycholic acid, and both were decreased by ethinyl estradiol treatment. During [24-14C]sodium deoxycholate infusion, [14C]biliary bile acid secretion increased, but bile flow did not change significantly in either control or ethinyl estradiol-treated rats. Ethinyl estradiol-treated animals excreted significantly less 14C as taurocholic acid than did control animals, consistent with an impairment of 7alpha-hydroxylation of taurodeoxycholic acid. Ethinyl estradiol treatment did not impair conjugation of deoxycholic acid, but did result in an increase in sulfation of taurodeoxycholic acid from 1.5% in controls to nearly 4.0% (P less than 0.01). These results are consistent with the hypothesis that the rat has a poorer tolerance for deoxycholic acid than do certain other species. Furthermore, the rat converts deoxycholic acid, a poor choleretic, to taurocholic acid, a good choleretic. When this conversion is impaired with ethinyl estradiol treatment, sulfation may be an important alternate pathway for excretion of this potentially harmful bile acid.

Effects of ethinylestradiol-induced cholestasis on bile flow and biliary excretion of estradiol and estradiol glucuronide by the rat.

SummaryThe effects of ethinylestradiol treatment on bile flow and biliary excretion of bromsulfophthalein, estradiol, and estradiol glucuronide in the rat were studied. One day following 9 days of 0.5 mg of ethinylestradiol treatment, bile duct cannulation and femoral vein catheterization were carried out. From that time until the end of study, bile flow was strikingly reduced in the estrogen-treated animals to less than 50% of that in the control group. One day following surgery, studies of biliary excretion were performed revealing a markedly diminished biliary excretion of radioactivity from intravenously administered tracer doses of both estradiol and estradiol glucuronide in the treated animals. The effect of estrogen treatment on bile flow and estrogen excretion in the bile is similar to that previously observed for bromsulfophthalein clearance. Possible mechanisms of estrogen action and implications in human estrogen-induced cholestasis are discussed.