Estradiol–17β–D–Glucuronide (E–17G) Cholestasis in Perfused Rat Liver: Fate of E–17G and Choleretic Responses to Bile Salts

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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.)