Ursodeoxycholate (UDC) prevents Mrp2 activity impairment in ethinylestradiol (EE)-induced cholestasis.

SÁNCHEZ POZZI, ENRIQUE J; D'ANDREA, VANESA; CROCENZI, FERNANDO A; PELLEGRINO, JOSÉ M; LUQUITA, MARCELO G.; CATANIA, VIVIANA A.

Salvador, Bahía, Brasil

Congreso; Biennial Scientific Meeting of the International Association for the Study of the Liver (IASL).; 2004

International Association for the Study of the Liver (IASL)

EE administration induces cholestasis by affecting both bile salt-dependent and bile salt-independent fractions of the bile flow. The decrease in bile salt-independent flow is thought to be due, in part, to a reduction in the expression of the canalicular transporter Mrp2. UDC administration reverts estrogen-induced decrease in bile flow, but, despite the role of Mrp2 in bile formation, the effect of UDC on this transporter in this model of cholestasis has not been analyzed as yet. The aim of this study was to analyze the protective effect of UDC on EE-induced impairment of Mrp2 transport activity, using the Mrp2 model substrate dinitrophenyl-glutathione (DNPG). Methodology: Male Wistar rats were divided in 3 experimental groups: i) rats receiving EE (5 mg/kg bw, sc, for 5 days) and UDC (25 mg/kg bw, ip, for 5 days) (EU), ii) rats receiving EE and solvent (E) and iii) rats receiving solvent alone (C). On the sixth day, a basal 10-min period of bile was collected and next, rats were injected with 1-chloro-2,4-dinitro-benzene (CDNB, 10 µmol/kg bw, iv). This compound is conjugated in the liver, rendering DNPG. Excretory kinetics were assessed by collecting bile every 10 min for 60 min, and next, a liver sample was obtained. DNPG concentration was measured by HPLC. Results (mean±SD, n=3): EE reduced DNPG excretion (µmol/kg bw) by 55 % and UDC fully restored the alteration (C: 2.7±0.1, E: 1.2±0.4a, EU 2.2±0.4b). Hepatic content of DNPG (nmol/kg bw) was increased by EE and reverted to control values by UDC (C: 99±39, E: 185±15a, EU: 129±17b). (a) significantly different from C, (b) significantly different from E (p<0.05). Conclusion: EE administration reduced Mrp2 activity which led to an impairment in the excretion of DNPG and to an increase in amount of this compound retained in the liver. UDC restored transport activity, thus explaining, at least in part its beneficial effect in this model of cholestasis.