Estrogen stimulation of 3-o-methyl-D-glucose uptake in isolated rat hepatocytes

The effect of in vivo and in vitro estrogen treatment on 3-O-methyl-D-glucose (30MDG) uptake in isolated rat hepatocytes was examined. A 1-h preincubation of isolated hepatocytes with 17 beta-estradiol (E2) or 17 alpha-ethynyl estradiol stimulated uptake of 30MDG in a dose-dependent fashion. The response appeared to be sterospecific, in that 17 alpha-estradiol was approximately 100-fold less effective than its 17 beta isomer. By itself, the triarylethylene antiestrogen, nafoxidine, slightly increased hepatocyte 30MDG uptake, while in combination with estrogen, nafoxidine completely blocked the effects of both E2 and 17 alpha-ethynyl estradiol. The protein synthesis inhibitor, cycloheximide, inhibited basal 30MDG uptake and abolished the stimulatory effect of estrogen. Kinetic analysis indicated that the estrogen effect resulted from an increase in the Vmax of the 30MDG transport system, with no measurable change in its Km. In vivo estrogen treatment, using either estrogen injections or continuous release Silastic E2 capsules, produced an increase in hepatocyte 30MDG uptake of 52-86%. A similar (66%) increase was seen in pregnant animals between the 14th and 19th days of gestation. These findings demonstrate that estrogens exert a rapid stimulatory effect on hepatocyte hexose transport. This effect is qualitatively similar to the response to estrogen of the hexose transport systems in other estrogen target tissues, such as the uterus. In addition, the results provide further support for the concept that the effects of the triarylethylene antiestrogens are both tissue and end-point dependent. Although previous studies have shown that nafoxidine exerts estrogen-like effects on hepatic renin substrate production, the present data indicate that, with respect to hepatocyte 30MDG, nafoxidine is almost a pure estrogen antagonist.