The human growth hormone (hGH) antagonist (G120R)hGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor

Human GH (hGH) acts by dimerizing two hGH receptors that bind to different sites in hGH. (G120R)hGH, an analog mutated in the second binding site to prevent receptor dimerization, acts as an antagonist in vitro. We have now tested the activity of this analog in vivo in rats with low or absent endogenous GH secretion. Surprisingly, treatment with (G120R)hGH failed to antagonize the effects of infusions or injections of hGH in hypophysectomized (Hx) rats and had little effect on hepatic OH-sensitive CYP2C transcripts in GK-deficient dwarf(dw) rats. Paradoxically, (G120R)hGH stimulated skeletal growth when infused into Hx rats; a pulsatile iv infusion was more affective than a continuous pattern. Coinfusion of (G120R)hGK With hGH produced an additive effect on growth. In addition, continuous, but not pulsatile, (G120R)hGH infusion elevated hepatic 2C12 messenger RNA (mRNA) expression and reduced 2C11 mRNA expression in Hx rats. The direct effects of (G120R)hGH on hepatic CYP2C transcripts were confirmed in cultured hepa tocytes in vitro, which also revealed a significant action of PRL in elevating 2C12 mRNA expression. Binding studies revealed that (G120R)hGH bound preferentially to hepatic PRL receptors, as [I-125](G120R)hGH was completely displaced by ovine PRL but was unaffected by bGH, a specific GH receptor ligand. The weak growth-promoting effects of (G120R)hGH were similar to those induced by recombinant hPRL in Hx rats. Our results show that (G120R)hGH is a poor in vivo GH antagonist in the rat, but shows a paradoxical agonist effect, probably mediated by PRL receptors in this species.