Hepatotoxic effects of estradiol-17β-D-glucuronide in the rat and monkey

The steroid D-ring glucuronide conjugate estradiol-17β-D-glucuronide (E ₂17G) but not the A-ring conjugate E ₂3-glucuronide (E ₂3G) has been shown to inhibit bile flow in the rat. To determine if primates are also sensitive to E ₂17G-induced cholestasis, a noninvasive approach with the use of indocyanine green (ICG), a dye eliminated primarily by biliary excretion, was first validated in the rat then applied to the rhesus monkey. ICG (16 mg/kg rat; 4 mg/kg monkey) was administered i.v. 10 min after an i.v. bolus dose of either E ₂17G (5.5 or 11 μmol/kg), E ₂3G (11 μmol/kg) or vehicle alone. In the rat, the elimination T( 1/2 ) of ICG was increased by the 11 μmol/kg dose of E ₂17G (P < .025), whereas E ₂3G produced no significant change from vehicle control values. In the monkey, the 5.5 and 11 μmol/kg doses of E ₂17G increased the T( 1/2 ) of ICG in a dose-related manner (P < .005), whereas E ₂3G was without effect. Plasma levels of total radioactivity demonstrated dose-dependent kinetics after the administration of a tracer dose and 11 μmol/kg of [ ³H]E ₂17G. A rebound of plasma radioactivity was seen at 11 μmol/kg of [ ³H]E ₂17G, the time course of which mimicked the time course of E ₂17G-induced cholestasis. High-performance liquid chromatographic analysis of rat bile and plasma after the administration of [ ³H]E ₂17G revealed primarily E ₂17G and estradiol-3-sulfate-17β-D-glucuronide together with small amounts of three unidentified metabolites. In the monkey, only E ₂17G and estradiol-3-sulfate-17β-D-glucuronide were observed in the plasma after the administration of [ ³H]E ₂17G. In contrast to E ₂17G, estradiol-3-sulfate-17β-D-glucuronide was choleretic in the bile duct-cannulated rat model. These data indicate that E ₂17G is hepatotoxic in both rodents and nonhuman primates.