The metabolism of oestrone and some other steroids in isolated perfused rat and guinea pig livers

Abstract

1. Oestrone is rapidly taken up by isolated perfused rat liver (t_1/2< 2 min) to yield at least 10 metabolites excreted in the bile; peak concentration occurs after about 20 min.

2. Sulphated metabolites of oestrone appear in the perfusate, reaching peak concentration at about 10 min, and then slowly disappear.

3. Sulphated metabolites of oestrone accumulate in the liver during the first 10 min. They are partly converted to sulphoglucuronides (steroid 3-sulphates conjugated with glucuronic acid in the D ring) and partly hydrolysed to be reconjugated as glucuronides.

4. The major biliary metabolites of oestrone in isolated perfused rat liver are glucuronides and sulphoglucuronides, but free steroids, sulphates and polar metabolites are also so excreted.

5. The isolated perfused guinea pig liver also rapidly takes up oestrone (t_1/2 < 2 min) but, in contrast to the rat, a single glucuronide is the only quantitatively important metabolite in the bile: it is also extensively secreted into the perfusate where it reaches peak concentration at about 10 min.

6. In perfused guinea pig liver, oestrone does not form sulphoglucuronides, and sulphates are only minor metabolites; this is not due to lack of the appropriate sulphotransferase because oestradiol 17β-(β-D-glucuronide) is extensively sulphated in this system.

7. Oestradiol 17β-(β-D-glucuronide) is not cholestatic in the isolated perfused guinea pig liver although it is in rat liver.

8. There is a similar species difference in the metabolism of dehydroepiandrosterone in the two species: the rat forms sulphoglucuronides, the guinea pig does not.

9. The perfused rat liver extensively hydroxylates, presumably on the D ring, 17-deoxyoestrone and 17-deoxydehydroepiandrosterone.

10. The inability of perfused guinea pig liver to form sulphoglucuronides from oestrone or dehydroepiandrosterone is probably due to its restricted ability to hydroxylate the D ring of steroids.

11. Both rat and guinea pig biles contain β-glucuronidase, about 80 and 230 sigma units/ml, respectively.