Simultaneous perfusion of [4-14C]oestriol and [6,9-3H2]oestriol 16α-monoglucuronide through the isolated rat liver

Abstract

Abstract. Equimolar concentrations of [4-14C]oestriol and [6,9-3H2]oestriol 16α-monoglucuronide were simultaneously perfused through isolated rat livers. Oestriol was hydroxylated to 2-hydroxyoestriol and 6ξ-hydroxyoestriol; 2-hydroxyoestriol was further methylated to 2-methoxyoestriol. Oxidoreduction of oestriol led to the formation of 16α-hydroxyoestrone, 16-oxooestradiol-17β and 16-epioestriol. In addition, two dehydroxylation products, namely oestrone and oestradiol-17β were found. The metabolites formed from oestriol were partly conjugated to monoglucuronides, monosulphates and sulphoglucuronides. About 80% of the oestriol perfused was hydroxylated at C-atom 2. Most of the 2-hydroxyoestriol formed was either methylated (about 37%) or sulphated (about 55%). Only small amounts (less than 2%) of the catecholoestrogens formed were methylated as well as sulphated. The 2-hydroxyoestriol monosulphates accumulated in the liver. After their conjugation with glucuronic acid, the double conjugates formed were immediately excreted into the bile. In fact, 2-hydroxyoestriol 16α-monoglucuronide 2(3?)-monosulphate comprised by far the main biliary metabolite of [4-14C]oestriol, followed by oestriol 16α-monoglucuronide and 2-methoxyoestriol 16α-monoglucuronide. No tritiated sulphoglucuronides were detected, thus indicating that the monosulphates are the immediate precursors of the double conjugates. [6,9-3H2]Oestriol 16α-monoglucuronide was metabolised only to a small extent. After its uptake into the liver more than 90% of this conjugate was secreted unchanged into the bile. The remaining part was hydrolysed; the oestriol liberated followed the same metabolic reactions as those found for [4-14C]oestriol. This indicates that the 16α-glucuronide of oestriol is not metabolised to any appreciable extent.