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 stud ied in Ames dwarf mice, which do not express growth hormone (GH) or pr olactin (PRL) genes. Labeled GH was injected in low amounts that did n ot exceed the normal physiological GH concentration in mice. Binding o f most of the injected I-125-hGH by the GH-binding proteins (GHBPs) pr esent in plasma represents the first step in the handling of this mate rial in vivo. The decay curve followed a two-compartment model and gav e the equation: Conc = 2.807e(-0.0067t) + 15301e(-0.0647t) (coefficien t 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 c omplexes, presumably with GHBPs under in vivo conditions. The second s tep 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], respec tively) due to lower concentration of free GH in plasma and to the red uced number of GH-receptors (GHRs). The radioactive material present i n the liver was compatible with I-125-hGH-GHR complexes with Stokes ra dius of 59 Angstrom. In summary, we provide evidence that plasma of dw arf mice contains proteins capable of binding GH in vivo and probably representing GHBPs not complexed with GH. The presence of these protei ns modified the pharmacokinetics of I-125-hGH in plasma and its subseq uent uptake by the liver. The presence of these binding proteins in th e absence of endogenous GH suggests that a fraction of total GHBPs (on e class?) is independent of GH concentration.