Specific interactions of growth hormone (GH) with GH-receptors and GH-binding proteins in vivo in genetically GH-deficient Ames dwarf mice

The fate of exogenous radiolabeled growth hormone (I-125-hGH) was studied in Ames dwarf mice, which do not express growth hormone (GH) or, prolactin (PRL) genes; Labeled GH was injected in low amounts that did not exceed the normal physiological GH concentration in mice. Binding of most of the injected I-125-hGH by the GH-binding proteins (GHBPs) present in plasma represents the first step in the handling of this material in vivo. The decay curve followed a two-compartment model and gave the equation: Conc = 2.807e(-0 0067t) + 15301e(-0.0647t) (coefficient of determination 0.9986 +/- 0.0019), while in normal mice, GH decay followed a three-compartment model as we have previously reported. The fast compartment with t(1/2) of 1-2 min was virtually absent in dwarf mice, and chromatographic studies revealed the disappearance of free GH in these mice. We also present evidence of the labeled GH-forming complexes, presumably with GHBPs under in vivo conditions. The second step of processing labeled GH in vivo is the uptake by the liver, which was slower in dwarf than in normal mice (30-45 vs 15 min). Moreover, a lower GH uptake was found in dwarf than in normal mice (L/B ratio of 1.75 +/- 0.29 [30 min] vs L/B ratio of 3.68 +/- 0.33 [15 min], respectively) due to lower concentration of free GH in plasma and to the reduced number of GH-receptors (GHRs). The radioactive material present in the liver was compatible with I-125- hGH-GHR complexes with Stokes radius of 59 Angstrom. In summary, we provide evidence that plasma of dwarf mice contains proteins capable of binding GH in vivo and probably representing GHBPs not complexed with GH. The presence of these proteins modified the pharmacokinetics of I-125-hGH in plasma and its subsequent uptake by the liver. The presence of these binding proteins in the absence of endogenous GH suggests that a fraction of total GHBPs tone class?) is independent of GH concentration.