The kinetics of hepatocellular transport and metabolism of estrogens (comparison between estrone sulfate, estrone and ethinylestradiol)

Abstract

Abstract The turnover of estrone, estrone sulfate and ethinylestradiol∗ was studied in the whole rat and in isolated rat liver cells with regard to the sequential steps involved in hepatic uptake, metabolism and secretion of estrogens. After i.v. injection of estrone or estrone sulfate (5 nmol/250 g rat), the maximal biliary excretion of both compounds is observed within 20 min, and the fractions of biliary glucuronides (about 79%) and sulfates (about 19%) derived from the two estrogens, are almost identical. Isolated liver cells have preserved their ability to hydroxylate and conjugate estrogens and to release the newly formed conjugates. The major difference between the hepatocellular turnover of estrone and estrone sulfate is uptake, which proceeds much slower with the conjugated form. Uptake of estrone sulfate is followed by deconjugation. This can explain the similar conjugate patterns of metabolites derived from estrone and estrone sulfate in vivo. The free estrogens are conjugated within the isolated hepatocytes. The conjugates are released from the cells mainly as glucuronides (about 35%) and sulfates (about 13% in the case of estrone). The conjugation of ethinylestradiol is faster than conjugation of estrone and can be depressed by inhibitors of microsomal hydroxylation.