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Futile cycling of estrone sulfate and estrone in the recirculating perfused rat liver preparation.

The futile cycling of estrone sulfate (E(1)S) and estrone (E1) was investigated in the recirculating, perfused, rat liver preparation. Although E(1)S was not distributed into bovine erythrocytes, the compound was highly bound to albumin [4% bovine serum albumin (BSA), unbound fraction of 0.03 +/- 0.01]. By contrast, E1 was bound and metabolized to estradiol (E2) by bovine erythrocytes, with metabolic clearances of 0.061 to 0.069 ml/min when normalized to the hematocrit. Due to strong binding of E1 to albumin, BSA (4%) greatly reduced the red cell clearance to a minimum (0.0024 to 0.0031 ml/min/unit of hematocrit). Despite the low unbound fractions of E(1)S (0.027 +/- 0.004) and E1 (0.036 +/- 0.006), clearances of the simultaneously delivered tracers [(3)H]E(1)S and [(14)C]E1 in perfusate (4% BSA and 20% erythrocytes) by the recirculating, perfused rat liver (flow rate of 0.91 +/- 0.1 ml/min/g of liver) were high (0.53 +/- 0.08 and 0.85 +/- 0.2 ml/min/g of liver, respectively). Although low levels of [(3)H]E1 were observed following the tracer [(3)H]E(1)S, both parent and metabolite species displayed similar decay half-lives that were characteristic of compounds undergoing futile cycling. The same decay profile was observed for [(14)C]E(1)S but the half-life of administered [(14)C]E1 was shorter in comparison. A series-compartment liver model that incorporated previously noted heterogeneity in estrone sulfation and glucuronidation activities among periportal and perivenous hepatocytes, and homogeneity in sinusoidal transport and desulfation was used to explain the discrepant half-lives. The model described a high partitioning of E1 in the endoplasmic reticulum and the segregation of estrone sulfation activities in the cytosolic space from the desulfation and glucuronidation activities in the endoplasmic reticulum space.