Abstract

The metabolic activities and tissue binding of estrone (E₁) and estrone sulfate (E₁S) on futile cycling were examined. Desulfation of E₁S in the 9000g supernatant fraction (S9) of periportal (PP) and perivenous (PV) rat hepatocytes were of similarV maxE1S→E1 (2.9 ± 1.0 and 2.4 ± 0.9 nmol/min/mg of S9 protein),K mE1S→E1 (30.4 ± 8.3 and 34.8 ± 6.6 μM), and desulfation intrinsic clearances (V maxE1S→E1 /K mE1S→E1 of 77 and 55 μl/min/10⁶ cells). The intrinsic clearance towards E₁ sulfation (1 μM) in cytosolic preparations of PV hepatocytes was 4 times that of PP hepatocytes (V maxE1→E1S /K mE1→E1S of 26.4 ± 9.5 versus 6.1 ± 2.2 μl/min/mg of cytosolic protein or 13 ± 5 versus 3.1 ± 1.1 μl/min/10⁶cells). The observation was consistent with the immunolocalization of estrogen sulfotransferase (PV/PP ratio of 3.4 ± 1.1) but not hydroxysteroid sulfotransferase (PV/PP ratio of 0.29 ± 0.21) nor phenol sulfotransferase (PV/PP ratio of 1.13 ± 0.23). Upon incubation of E₁S (1–125 μM) with hepatocytes (30 min), higher concentrations of E₁S and E₁ were observed within PP than in PV cells, and saturation was evident at the higher concentrations. Based on the in vitro metabolic and tissue binding parameters for E₁S and E₁ and the published zonal uptake clearances of E₁S (116 μl/min/10⁶ cells), fitting revealed that uptake of E₁ (1484 and 1463 μl/min/10⁶ cells) by PP and PV cells was rapid and similar, and E₁ sulfation was the slowest step in futile cycling. The greater metabolism of E₁ in PV region led to higher levels of E₁ and E₁S in PP hepatocytes, and the nonlinear uptake, binding, and vesicular accumulation of E₁S resulted in differentt_1/2 values for E₁S and E₁.