Metabolic Clearance Rate and Uterotropic Activity of 2-Hydroxyestrone in Rats

2-Hydroxyestrone (2-OHE₁) has much lower uterotropic potency than might be predicted from its uterine estrogen receptor affinity. 2-OHE₁ displaces saturably bound [³H]estradiol from rat uterine cytosol with a competitive inhibition constant of 8.6 nm, while the dissociation constant for 17β- estradiol (E₂) is 0.42 nM. From this ratio of binding affinities, one would expect some agonist or antagonist activity of 2-OHE₁ to be apparent at doses roughly 20-50 times the minimum effective dose of E₂. Instead, at doses of 2-OHE₁ 1000 times an effective dose of E₂, no uterotropic effect was observed. When 2-OHE₁ was injected together with E₂ at dose ratios of 500:1, there was no antagonism of the effect of E₂. To examine this discrepancy, the plasma MCRs (MCR_ps) of E₂ and 2-OHE₁ were determined by continuous infusion techniques. Plasma concentrations of 2-OHE₁ and E₂ during control and infusion periods were measured by RIAs. The MCR_p of 2- OHE₁ averaged 50, 000 ml/h, more than 100 times that of E₂ (-400 ml/h). The extraordinarily high MCR_p of 2-OHE₁ may explain the failure to observe any biological effects of this catechol estrogen, even at high doses. This rapid metabolism, presumably occurring in the blood compartment, should be considered in handling blood samples for RIA and in devising studies of the actions of catechol estrogens.