Estradiol-17β-D-glucuronide (E-17G) cholestasis in perfused rat liver: Fate of E-17G and choleretic responses to bile salts

Abstract

This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug-induced cholestasis. Cholestasis was induced by administration of 17.5 μmol/L estradiol-17β-D-glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 μmol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose-dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose-dependent recovery. Further increase of tauroursodeoxycholate infusion rate to 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradio-17β-D-glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol-17β-D-glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol-17β-D-glucuronide declined significantly, and a marked back-efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol-17β-D-glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back-efflux of estradiol-17β-D-glucuronide at the two highest tauroursodeoxycholate infusion rates. Dehydrocholate, at higher infusion rates, did not enhance estradiol-17β-D-glucuronide biliary transport or regurgitation. The effects of taurocholate, tauroursodeoxycholate and dehydrocholate on bile flow, bile salt secretion and estrogen excretion during estradiol-17β-D-glucuronide cholestasis paralleled their relative hydrophobicity and detergent effect. Taurocholate infusion also decreased the adverse effect of estradiol-17β-D-glucuronide on sucrose clearance. Among the bile salts used, taurocholate was the most effective in increasing bile flow during estradiol-17β-D-glucuronide cholestasis but showed some toxicity. Although less effective, tauroursodeoxycholate did not exert adverse effects. Accordingly, tauroursodeoxycholate has a higher therapeutic index that might be relevant in efforts to treat estrogen-induced cholestasis by administration of bile salts.(HEPATOLOGY 1990; 11:735-742.)