PT - JOURNAL ARTICLE AU - Eugene Tan AU - K. Sandy Pang TI - Sulfation is Rate Limiting in the Futile Cycling Between Estrone and Estrone Sulfate in Enriched Periportal and Perivenous Rat Hepatocytes DP - 2001 Mar 01 TA - Drug Metabolism and Disposition PG - 335--346 VI - 29 IP - 3 4099 - http://dmd.aspetjournals.org/content/29/3/335.short 4100 - http://dmd.aspetjournals.org/content/29/3/335.full SO - Drug Metab Dispos2001 Mar 01; 29 AB - 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 differentt1/2 values for E1S and E1. The American Society for Pharmacology and Experimental Therapeutics