Improvement of estradiol 17β-D-glucuronide cholestasis by intravenous administration of dimethylethanolamine in the rat

Abstract

The intravenous administration of dimethylethanolamine in the rat promotes a selective enrichment of liver membranes with polyunsaturated phosphatidylcholines. The effect of dimethylethanolamine pretreatment on cholestasis induced by estradiol 17 beta-D-glucuronide, a potent cholestatic agent, was assessed in this study. Dimethylethanolamine, dissolved in sodium-taurocholate was infused intravenously (0.3 mg/kg/min) for 15 hr. One group of control rats (estradiol 17 beta-D-glucuronide controls) received the bile salt only. An estradiol 17 beta-D-glucuronide bolus was then injected intravenously (10.4 mg/kg) into dimethylethanolamine-pretreated and estradiol 17 beta-D-control rats, and its effect on bile flow and biliary lipid secretion was compared for 3 hr. The estradiol 17 beta-D-glucuronide inhibitory effect on bile flow and biliary lipid secretion was significantly antagonized by dimethylethanolamine pretreatment. The maximum inhibition of bile flow was found 30 min after estradiol 17 beta-D-glucuronide administration, when it decreased from 3.5 +/- 0.4 microliters/min/100 gm (basal) to 0.9 +/- 0.3 microliters/min/100 gm in estradiol 17 beta-D-glucuronide controls, whereas in dimethylethanolamine-pretreated rats this decreased only from 3.2 +/- 0.4 (basal) to 2.3 +/- 0.4 microliters/min/100 gm. Bile flow and the biliary secretion of cholesterol, phosphatidylcholine and bile salts were significantly higher in the dimethylethanolamine-pretreated rats than in estradiol 17 beta-D-glucuronide controls (p less than 0.02) during the cholestatic phase. The inhibitory effect of estradiol 17 beta-D-glucuronide on bile flow was associated with a marked decrease of membrane fluidity (p less than 0.001) assessed by 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and with a cholesterol enrichment of microsomes, sinusoidal and canalicular liver plasma membranes and inhibition of sinusoidal Na+,K(+)-ATPase activity (p less than 0.05). These membrane alterations persisted 180 min after estradiol 17 beta-D-glucuronide administration despite complete normalization of bile flow. Dimethylethanolamine pretreatment significantly counteracted the reduction of membrane fluidity (p less than 0.001), the cholesterol enrichment and the inhibition of Na+,K(+)-ATPase (p less than 0.05) promoted by estradiol 17 beta-D-glucuronide administration in all membrane subfractions 30 and 180 min after administration. In addition, dimethylethanolamine-pretreated rats had more polyunsaturated fatty acids in membrane phosphatidylcholine with respect to the control groups. Dilatation of canaliculi and loss of microvilli were evident in estradiol 17 beta-D-glucuronide controls 180 min after estradiol 17 beta-D-glucuronide administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Hepatic pharmacokinetics of taurocholate in the normal and cholestatic rat liver

“…The underlying mechanism is still not fully elucidated, but D‐ring glucuronide conjugates such as estradiol 17 β ‐glucuronide have been implicated as causative agents (Meyers et al ., 1980; Vore et al ., 1983). It has been suggested that estrogen glucuronides impair bile salt excretion (Adinolfi et al ., 1984), increase the permeability of tight junctions (Kan et al ., 1989), decrease bile flow (Meyers et al ., 1980; Vore et al ., 1983) and sinusoidal membrane fluidity (Alvaro et al ., 1991). In cholestasis transport of bile salts such as taurocholate (TC) is affected.…”

Biliary excretory function is regulated by canalicular membrane fluidity associated with phospholipid fatty acyl chains in the bilayer: Implications for the pathophysiology of cholestasis

“… 19 Similarly, Alvaro et al found that determinants of canalicular membrane fluidity include both rate of motion and angular range of motion of the fatty acyl chains. 20 Therefore, membrane fluidity depends on the proportion of fatty acyl chains in the phospholipids of the bilayer. In this regard, we have examined causal relationships between cholestasis and membrane fluidity as defined by fatty acyl chains.…”

“… 19 According to Alvaro et al determinants of canalicular membrane fluidity include both the rate of motion and the angular range of motion of fatty acyl chains, which in turn depend on the proportion of polyunsaturated fatty acids in the membrane. 20 We conducted the present study to clarify the relationship between cholestasis and lipid metabolism using a rat model of acute phalloidin‐induced cholestasis. Cholesterol and phospholipid content, including the fatty acid composition in PC and sphingomyelin species of bile, canalicular membranes and microsomes (membrane fluidity) were analysed to elucidate whether the mechanism of cholestasis affects phospholipid fatty acid composition and membrane fluidity.…”

Role of bile salt hydrophobicity in distribution of phospholipid species to carriers in supersaturated model bile solutions

“…This might lead to a reduction of cholesterol packing density within a vesicular lipid membrane, in association with a tendency to release cholesterol molecules, since phospholipid hydrophobicity determines the cholesterol‐holding capacity of the lipid bilayer. In fact, changes of the phospholipid species in lipid bilayers have been found to alter the fluidity and/or permeability of the canalicular membrane and biliary vesicles 27 . This raises another possibility, that the production of mucin, one of the effector substances in cholesterol crystallization, could be stimulated in the gallbladder and secreted into bile.…”