A B S T R A C T These studies were undertaken to investigate (a) the permeability properties of the bloodbrain barrier (BBB) to the major gonadal and adrenal steroid hormones, and (b) the role of the binding proteins of plasyna (albumin and specific globulins) in the regulation of BBB steroid hormone transport.The testosterone, 85+1%; estradiol, 83+3%; corticosterone, 39±2%; aldosterone, 3.5±0.8%; and cortisol, 1.4±0.3%. The selective permeability of the BBB was inversely related to the number of hydrogen bonds each steroid formed in aqueous solution and directly related to the respective I-octanol/Ringer's partition coefficient.When the bolus injection was 67% human serum, >95% of the labeled steroid was bound as determined by equilibrium dialysis. However, the influx of the steroids through the BBB was inhibited by human serum to a much less extent than would be expected if only the free (dialyzable) hormone was transported; progesterone, estradiol, testosterone, and corticosterone transport was inhibited 18, 47, 70, and 85% respectively, or in proportion to the steroid binding to plasma globulins. Rat serum (67%) only inhibited the transport of these four hormones, 0, 13, 12, and 69%, respectively, reflecting the absence of a sex hormone-binding globu- KD(app), to the in vitro KD was: >200 for progesterone, >200 for testosterone, 120 for estradiol, and 7.7 for corticosterone. Assuming the steady-state condition, the KD(app)/KD was found to be proportional to the BBB permeability for each steroid.These data demonstrate (a) the selective permeability properties ofthe BBB to the major steroid hormones is proportional to the tendency ofthe steroid to partition in a polar lipid phase and is inversely related to the number of hydrogen bond-forming functional groups on the steroid nucleus; (b) the presence of albumin in serum may bind considerable quantities of steroid hormone, but exerts little inhibitory effects on the transport of steroids into brain, whereas globulin-bound hormone does not appear to be transported into brain to a significant extent. Therefore, the hormone fraction in plasma that is available for transport into brain is not restricted to the free (dialyzable) fraction, but includes the larger albumin-bound moiety.

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Recent studies indicate the lumped constant (LC), which defines the relative rates of brain utilization of glucose and 2-deoxyglucose (2-DG), doubles to values greater than 1.0 under conditions of hypoglycemia. Since changes in the LC should be predictable given the kinetic parameters of blood-brain barrier (BBB) transport and brain phosphorylation of glucose and 2-DG, the present studies were designed to measure the necessary kinetic parameters. The carotid injection technique ws used to determine cerebral blood flow and the Km, Vmax, and KD of glucose and 2-DG transport through the BBB in seven brain regions in rats anesthetized with 50 mg/kg i.lp. pentobarbital. Regional glucose transport through the BBB was characterized by an average Km = 6.3 mM, average Vmax = 0.53 mumol min-1g-1, and average KD = 0.022 ml min-1g-1.l The nonsaturable route of transport of glucose represented on the average 40% of the total glucose influx into brain regions at an arterial glucose concentration of 10 mM. In addition, the rate constants of phosphorylation of glucose and 2-DG were measured for each region. Substitutions of the measured kinetic parameters for sugar transport and phosphorylation into equations defining the LC confirm the observation that the LC would be expected to vary under extreme conditions such as hypoglycemia and to exceed values of 1.0 under these conditions.

The unidirectional influx of 3H-gonadal (progesterone, dihydrotestosterone, testosterone, estradiol) and adrenal (aldosterone, cortisol) steroid hormones into liver was studied with a tissue-sampling single-injection technique in barbiturate-anesthetized rats. Liver uptake of the steroid hormone was measured relative to [14C]butanol, a highly diffusible reference, after a single pass through the liver. Portal flow (1.4 ml.min-1.g-1) under the experimental conditions was measured with 3H2O. The extraction of unidirectional influx of all six steroid hormones was 70-100% after a bolus portal injection of labeled steroid in Ringer solution (0.1% albumin). Steroid transport was nonsaturable because 35 muM concentrations of unlabeled hormone resulted in no inhibition of liver transport. The plasma proteins (albumin and specific globulins) in serum from human (male, female, pregnancy), rat (male), and guinea pig (pregnancy) sources inhibited the liver clearance of the respective steroid hormones to a variable extent. In all cases albumin-bound steroid hormone was freely cleared by liver and, in the case of cortisol or estradiol, the fraction bound to a specific globulin was also transported into liver.