Inhibition of biliary bicarbonate secretion in ethinyl estradiol-induced cholestasis is not associated with impaired activity of the Cl−/HCO3− exchanger in the rat

Alvaro, Domenico; Gigliozzi, Alessandro; Piat, Claudia; Carli, Laura De; Fraioli, F; Roméo, R; Francia, Chiara; Attili, Adolfo Francesco; Capocaccia, L.

doi:10.1016/s0168-8278(97)80021-9

Cited by 19 publications

(20 citation statements)

References 34 publications

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“…As previously reported, EE impaired BSIF by diminishing the biliary excretion of glutathione (Bouchard et al, 1994) and HCO 3 Ϫ (Alvaro et al, 1997), two compounds thought to be mainly responsible for this fraction of bile flow. Impairment of BSIF by EE was also partially protected by GAL, which reverted the effects of the estrogen on HCO 3 Ϫ excretion but not on glutathione output.…”

Section: Discussionsupporting

confidence: 75%

“…Impairment of BSIF by EE was also partially protected by GAL, which reverted the effects of the estrogen on HCO 3 Ϫ excretion but not on glutathione output. Because Western blot analysis demonstrated that anion exchanger 2, the canalicular transporter of HCO 3 Ϫ , is preserved in EE cholestasis (Alvaro et al, 1997), a functional alteration of the transporter could be responsible for HCO 3 Ϫ excretion impairment. GAL prevention of estrogen-induced alteration in HCO 3 Ϫ excretion suggests that EE-glucuronide could participate in the alleged functional alteration of the transporter, although the mechanism remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Crocenzi

Pellegrino²,

Catania³

et al. 2006

Drug Metab Dispos

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not alter any of the serum markers of liver injury studied (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) or biliary secretory function. When coadministered with EE, galactosamine partially prevented the impairment induced by this estrogen in total bile flow, the bile-salt-independent fraction of bile flow, basal bile salt secretion, and the secretory rate maximum of tauroursodeoxycholate. Uridine coadministration partially prevented galactosamine from exerting its anticholestatic effects. In conclusion, galactosamine administration partially prevented EE-induced cholestasis by a mechanism involving decreased UDP-GA availability for subsequent formation of EE 17␤-glucuronide. The evidence thus supports the hypothesis that EE 17␤-glucuronide is involved in the pathogenesis of EE cholestasis.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Crocenzi

Pellegrino²,

Catania³

et al. 2006

Drug Metab Dispos

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“…As reported here for AQP8, the canalicular transport proteins Bsep and Mrp2 are downregulated (23,39), although the expression of Bsep is relatively preserved compared with Mrp2. Even though the HCO 3 Ϫ excretion is impaired in EE-treated rats, the functional activity of the Cl Ϫ /HCO 3 Ϫ exchanger AE2 was found not to be affected by EE (1). In contrast to the lack of effect of EE-treatment on basolateral AQP9, the expression of the solute basolateral transporters, Na ϩ taurocholate cotransporting polypeptide Ntcp, and the Na ϩ -independent organic anion transporting polypeptide Oatp were significantly reduced (17,37).…”

Section: Discussionmentioning

confidence: 81%

Defective hepatocyte aquaporin-8 expression and reduced canalicular membrane water permeability in estrogen-induced cholestasis

Carreras¹,

Lehmann²,

Ferri³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Carreras FI, Lehmann GL, Ferri D, Tioni MF, Calamita G, Marinelli RA. Defective hepatocyte aquaporin-8 expression and reduced canalicular membrane water permeability in estrogeninduced cholestasis. Am J Physiol Gastrointest Liver Physiol 292: G905-G912, 2007. First published November 16, 2006; doi:10.1152/ajpgi.00386.2006.-Our previous work supports a role for aquaporin-8 (AQP8) water channels in rat hepatocyte bile formation mainly by facilitating the osmotically driven canalicular secretion of water. In this study, we tested whether a condition with compromised canalicular bile secretion, i.e., the estrogen-induced intrahepatic cholestasis, displays defective hepatocyte AQP8 functional expression. After 17␣-ethinylestradiol administration (5 mg ⅐ kg body wt Ϫ1 ⅐ day Ϫ1 for 5 days) to rats, the bile flow was reduced by 58% (P Ͻ 0.05). By subcellular fractionation and immunoblotting analysis, we found that 34 kDa AQP8 was significantly decreased by ϳ70% in plasma (canalicular) and intracellular (vesicular) liver membranes. However, 17␣-ethinylestradiol-induced cholestasis did not significantly affect the protein level or the subcellular localization of sinusoidal AQP9. Immunohistochemistry for liver AQPs confirmed these observations. Osmotic water permeability (P f) of canalicular membranes, measured by stopped-flow spectrophotometry, was significantly reduced (73 Ϯ 1 vs. 57 Ϯ 2 m/s) in cholestasis, consistent with defective canalicular AQP8 functional expression. By Northern blotting, we found that AQP8 mRNA expression was increased by 115% in cholestasis, suggesting a posttranscriptional mechanism of protein level reduction. Accordingly, studies in primary cultured rat hepatocytes indicated that the lysosomal protease inhibitor leupeptin prevented the estrogen-induced AQP8 downregulation. In conclusion, hepatocyte AQP8 protein expression is downregulated in estrogeninduced intrahepatic cholestasis, presumably by lysosomal-mediated degradation. Reduced canalicular membrane AQP8 expression is associated with impaired osmotic membrane water permeability. Our data support the novel notion that a defective expression of canalicular AQP8 contributes as a mechanism for bile secretory dysfunction of cholestatic hepatocytes.aquaporins; intrahepatic cholestasis; water transport; liver AQUAPORIN (AQP) water channels are a family of integral membrane proteins known to facilitate the osmotic water movement across the cellular membranes (3). Three members of the AQP family are expressed in rat hepatocytes: AQP8 (7, 13, 16, 21), AQP9 (14, 21, 40), and AQP0 (21). AQP8 is localized in the canalicular plasma membrane domain (7,13,16,21) as well as in intracellular vesicles (7,13,16,21) and mitochondria (6). Its trafficking from a vesicular compartment to the canalicular membrane can be induced by a choleretic stimulus, such as dibutyryl-cAMP (16,21) or the hormone glucagon (18,19,30). AQP9 resides exclusively on the sinusoidal plasma membranes of hepatocytes and thereby may facilitate the movement of water and certain small so...

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“…Additionally, HCO 3 Ϫ concentrations in bile were not different between the EE-treated and untreated rats, and HCO 3 Ϫ output therefore strongly correlated with bile flow rates, as recently reported by Alvaro et al in normal rats only. 48 So far, we have not been able to identify biliary component(s) that are specifically affected by EE both in NW and GY/TR Ϫ rats and, therefore, can be considered responsible for the reduced bile flow.…”

Section: Discussionmentioning

confidence: 98%

Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat

et al. 1998

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To test the hypothesis that impaired activity of the bile canalicular organic anion transporting system mrp2 (cmoat) is a key event in the etiology of 17␣-ethinylestradiol (EE)-induced intrahepatic cholestasis in rats, EE (5 mg/kg subcutaneously daily) was administered to male normal Wistar (NW) and mrp2-deficient Groningen Yellow/Transport-deficient Wistar (GY/TR ؊ ) rats. Elevated plasma bilirubin levels in GY/TR ؊ rats increased upon EE-treatment from 65 ؎ 8.4 mol/L to 183 ؎ 22.7 mol/L within 3 days, whereas bilirubin levels remained unaffected in NW rats. Biliary bilirubin secretion was 1.5-fold increased in NW rats but remained unaltered in GY/TR ؊ rats. Plasma bile salt concentrations remained unchanged in both strains, although hepatic levels of the sinusoidal Na ؉ -taurocholate cotransporting protein (ntcp) were markedly reduced. Biliary secretion of endogenous bile salt was not affected in either strain. A clear reduction of mrp2 levels in liver plasma membranes of NW rats was found after 3 days of treatment. The bile salt-independent fraction of bile flow (BSIF) was reduced from 2.6 to 2.0 L/min/100 g body weight in NW rats with a concomitant 62% reduction of biliary glutathione secretion. The absence of mrp2 and biliary glutathione in GY/TR ؊ rats did not prevent induction of EE-cholestasis; a similar absolute reduction of BSIF, i.e., from 1.1 to 0.6 L/min/100 g body weight, was found in these animals. EE treatment caused a reduction of the maximal biliary secretory rate (S RM ) of the mrp2 substrate, dibromosulphthalein (DBSP), from 1,040 to 695 nmol/min/ 100 g body weight (؊38%) in NW rats and from 615 to 327 nmol/min/100 g body weight (؊46%) in GY/TR ؊ rats. These results demonstrate that inhibition of mrp2 activity and/or biliary glutathione secretion is not the main cause of EE-induced cholestasis in rats. The data indicate that alternative pathways exist for the biliary secretion of bilirubin and related organic anions that are also affected by EE. (HEPATOLOGY 1998;27:537-545.)The synthetic estrogen, 17␣-ethinylestradiol (EE), causes a reversible intrahepatic cholestasis in experimental animals, mainly by reducing the bile salt-independent fraction of bile flow (BSIF). 1 Although EE-induced cholestasis has been claimed to represent a model of cholestasis of pregnancy in humans, 2 the mechanism(s) underlying the reduction in bile flow have not been defined. Suggestions that increased permeability of tight junctions 3,4 and reduced activity of Na ϩ / K ϩ -adenosine triphosphatase (ATPase) at the sinusoidal membrane 5-7 represent primary events in the onset of cholestasis could not be substantiated in more recent studies. [8][9][10][11] Likewise, the relevance of the reported decrease in sinusoidal membrane fluidity after EE treatment remains questionable, because decreased membrane fluidity has also been found in experimental conditions associated with increased bile flow. 11,12 More recently, it was shown that EE differentially affects the activity of transport systems involved in bile formation ...

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Inhibition of biliary bicarbonate secretion in ethinyl estradiol-induced cholestasis is not associated with impaired activity of the Cl−/HCO3− exchanger in the rat

Cited by 19 publications

References 34 publications

Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Galactosamine Prevents Ethinylestradiol-Induced Cholestasis

Defective hepatocyte aquaporin-8 expression and reduced canalicular membrane water permeability in estrogen-induced cholestasis

Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat

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