Transgenic Research

, Volume 2, Issue 4, pp 219–226 | Cite as

Pharmacokinetics of radioiodinated human and ovine growth hormones in transgenic mice expressing bovine growth hormone

  • D. Turyn
  • A. Bartke


Pharmacokinetics of radioiodinated human growth hormone (hGH) and ovine growth hormone (oGH) were studied in normal mice and in transgenic mice carrying the bovine growth hormone (bGH) gene fused to phosphoenolpyruvate carboxykinase promoter/regulator (PEPCK-bGH). Multiexponential plasma decay curves were obtained in both normal and transgenic mice after a125I-oGH injection and pharmacokinetic parameters were estimated by fitting blood concentration data to a three compartment model. The half-life for the rapid compartment was shorter in transgenic than in normal mice (t1/2γ:1.2±0.3 vs. 2.2±0.5 min). The slow compartment had a t1/2α of 160±23 min for transgenic and 70±8 min for normal mice while the middle compartment had a t1/2β of approximately 10 min for both groups of mice. The mean residence times were 167±24 and 55±5 min for transgenic and normal mice, respectively. Specific liver uptake of radioactivity after injection of125I-oGH or125I-hGH was found in both groups of animals. Specificity studies indicated that, similarly to normal mice, livers of transgenic mice possess a mixed population of somatotropic and lactogenic receptors. Uptake of labelled hGH by the liver was dose-dependent and the doses that prevented 50% of liver uptake (ED50%) were 8 and 165 μ g per 50 g body weight for normal and transgenic mice, respectively. Thesein vivo results confirm and extend previousin vitro findings that a life-long excess of bGH increases hepatic somatotropic and lactogenic receptors. Since elevation in growth hormone (GH) receptors was reported to be associated with an increase in GH binding protein (GHBP), we suspect that both the increase in the mean residence time and the reduction in specific uptake of GH in the livers of transgenic mice may be the result of an increase in GHBP levels.


GH receptors PRL receptors transgenic mice 


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  1. Aguilar, R.C., Fernandez, H.N., Dellacha, J.M., Calandra, R.S., Bartke, A. and Turyn, D. (1992a) Identification of somatogenic binding sites in liver microsomes from normal mice and transgenic mice expressing human growth hormone gene.Life Sci. 50, 615–20.CrossRefPubMedGoogle Scholar
  2. Aguilar, R.C., Fernandez, H.N., Dellacha, J.M., Calandra, R.S., Bartke, A., Ghosh, P.K. and Turyn, D. (1992b) Somatotropic and lactotropic receptors in transgenic mice expressing human and bovine growth hormone genes.Transgenic Res. 1, 221–7.PubMedGoogle Scholar
  3. Amit, T., Barkey, R.J., Gavish, M. and Youdim, M.B.H. (1984) Induction of prolactin (PRL) receptors by PRL in the rat lung and liver. Demonstration and characterization of a soluble receptor.Endocrinology 114, 545–52.PubMedGoogle Scholar
  4. Bartke, A., Naar, E.M., Johnson, L., May, H.R., Cecim, M., Yun, J.S. and Wagner, T.E. (1992) Effects of expression of human or bovine growth hormone genes on sperm production and male reproductive performance in four lines of transgenic mice.J. Reprod. Fert. 95, 109–18.Google Scholar
  5. Baumann, G., Stotlar, M.W., Amburn, K., Barsano, C.P. and De Vries, B.C. (1986a) A specific growth hormone binding protein in human plasma. Initial characterization.J. Clin. Endocrinol. Met. 6, 134–41.Google Scholar
  6. Baumann, G., Stotlar, M.W. and Buchanan, T.A. (1986b) The metabolic clearance, distribution and degradation of dimeric and mononeric growth hormone (GH): implications for the pattern of circulating GH forms.Endocrinology 119, 1497–501.PubMedGoogle Scholar
  7. Baumann, G., Amburn, K.D. and Buchanan, T.A. (1987) The effect of circulating growth hormone binding protein on metabolic clearance, distribution, and degradation of human growth hormone.J. Clin. Endocrinol. Metab. 64, 657–60.PubMedGoogle Scholar
  8. Bullier-Picard, F., Postel-Vinay, M.C. and Kayser, C. (1989)Invivo uptake of human growth hormone in male rat liver.J. Endocrinol. 121, 19–15.PubMedGoogle Scholar
  9. Chadwick, A., Folley, S.J. and Gemzell, C.A. (1961) Lactogenic activity of human pituitary growth hormone.Lancet 2, 241–43.CrossRefPubMedGoogle Scholar
  10. Chen, W.Y., White, M.E., Wagner, T.E. and Kopchick, J.J. (1991) Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice.Endocrinology 129, 1402–8.PubMedGoogle Scholar
  11. Ciccia-Torres, G.N., Turyn, D. and Dellacha, J.M. (1983) Mouse liver specific uptake of iodinated growth hormones: evidence for the presence of somatogenic and lactogenic sites.Horm. Metab. Res. 15, 443–8.PubMedGoogle Scholar
  12. Dave, J.R., Richardson, L.L. and Knazek, R.A. (1983) Prolactinbinding capacity, prostaglandin synthesis and fluidity of murine hepatic membranes are modified during pregnancy and lactation.J. Endocrinol. 99, 99–106.PubMedGoogle Scholar
  13. Herington, A.C., Phillips, L.S. and Daughaday, W.H. (1976a) Pituitary regulation of human growth hormone binding sites in rat liver membranes.Metabolism 25, 341–53.CrossRefPubMedGoogle Scholar
  14. Herington, A.C., Veith, N.M. and Burber, H.C. (1976b) Characterization of the binding of human growth hormone to microsomal membranes from rat liver.Biochem. J. 158, 61–9.PubMedGoogle Scholar
  15. Herington, A.C., Harrison, D. and Graystone, J. (1983) Hepatic binding of human and bovine growth hormones and ovine prolactin in the dwarf ‘little’ mouse.Endocrinology 112, 2032–8.PubMedGoogle Scholar
  16. Herington, A.C., Imer, S. and Stevenson, J. (1986) Identification and characterization of specific binding proteins for growth hormone in normal human sera.J. Clin. Invest. 77, 1817–23.PubMedGoogle Scholar
  17. Imer, S.J., Herington, A.C. (1985) Evidence for the specific binding of growth hormone to a receptor like protein in rabbit serum.Mol. Cell Endocrinol. 41, 153–62.CrossRefPubMedGoogle Scholar
  18. Johnson, T. and Maack, T. (1977) Renal extraction, filtration, absorption and catabolism of growth hormone.Am. J. Physiol. 233, F185-F196.PubMedGoogle Scholar
  19. Knazek, R.A., Liu, S.C., Graeter, R.L., Wright, P.C., Mayer, J.R., Lewis, R.H., Gould, E.B. and Keller, J.A. (1978) Growth hormone causes rapid induction of lactogenic receptor activity in the Snell dwarf mouse liver.Endocrinology 103, 1590–6.PubMedGoogle Scholar
  20. Li, C.H. (1972) Recent knowledge of the chemistry of lactogenic hormones. In Wolstenholm, G.E.W., Knight, J. eds.Lactogenic Hormones, pp. 7–26. London: Churchill Livingstone.Google Scholar
  21. Li, C.H. and Papkoff, H. (1956) Preparation and properties of growth hormone from human and monkey pituitary glands.Science 124, 1293–4.PubMedGoogle Scholar
  22. Li, C.H., Evans, H.M. and Simpson, M.E. (1945) Isolation and properties of the anterior hypophyseal growth hormone.J. Biol. Chem. 259, 353–66.Google Scholar
  23. Maiter, D., Underwood, L.E., Maes, M., Davenport, M.L. and Ketelslegers, J.M. (1988) Different effects of intermittent and continuous growth hormone (GH) administration on serum somatomedin-C/insulin-like growth factor I and liver GH receptors in hypophysectomized rats.Endocrinology 123, 1053–9.PubMedGoogle Scholar
  24. Mattera, R., Turyn, D., Fernández, H.N. and Dellacha, J.M. (1981) Structural characterization of iodinated bovine growth hormone.Int. Pept. Prot. Res. 19, 172–80.Google Scholar
  25. McGrane, M.M., de Vente, J., Yun, J., Bloom, J., Park, E., Wynshaw, A., Wagner, T., Rottman, F.M. and Hanson, R.W. (1988) Tissue-specific expression and dietary regulation of chimeric phosphoenolpyruvate carboxykinase/bovine growth hormone gene in transgenic mice.J. Biol. Chem. 16, 11443–51.Google Scholar
  26. Moore, J.A., Rudman, C.G., MacLachlan, N.J., Fuller, G.B., Burnett, B. and Frane, J.W. (1988) Equivalent potency and pharmacokinetics of recombinant human growth hormone with or without an N-terminal methionine.Endocrinology 122, 2920–6.PubMedGoogle Scholar
  27. Orian, J.M., Snibson, K., Stevenson, J.L., Brandon, M.R. and Herington, A.C. (1991) Elevation of growth hormone (GH) and prolactin receptors in transgenic mice expressing ovine GH.Endocrinology 128, 1238–46.PubMedGoogle Scholar
  28. Posner, B.I., Kelly, P.A., Shiu, R.P.C., Paud, R. and Friesen, H.G. (1974) Studies of insulin, growth hormone and prolactin binding sites: tissue distribution, species variation and characterization.Endocrinology 95, 521–31.PubMedGoogle Scholar
  29. Postel-Vinay, M.C., Kayser, C. and Desbuquois, B. (1982) Fate of injected human growth hormone in the female rat liverin vivo.Endocrinology 111, 244–51.PubMedGoogle Scholar
  30. Rabkin, R., Pimstone, B.L., Marks, T. and Eales, L. (1972) Disappearance of human growth hormone125I in the anephric non-uraemic and uraemic rat.Horm. Metab. Res. 4, 467–9.PubMedGoogle Scholar
  31. Ranke, M.B., Stanley, C.A., Rodbard, D., Baker, L., Bongiovanni, A. and Parks, J.S. (1976) Sex differences in binding of human growth hormone to isolated rat hepatocytes.Proc. Natl Acad. Sci. USA 73, 847–51.PubMedGoogle Scholar
  32. Retegui-Sardou, L.A., Scaramal, L.O., Dellacha, J.M. and Paladini, A.C. (1977) Rate of concentration and digestion of radioactive growth hormone preparations injected in rats, as measured by the amount and nature of radioactivity in the tissues.Mol. Cell Biochem. 16, 87–96.CrossRefPubMedGoogle Scholar
  33. Sanchez-Jimenez, F., Fielder, P.J., Martinez, R.R., Smith, W.C. and Talamantes, F. (1990) Hypophysectomy eliminates and growth hormone (GH) maintains the mid-pregnancy elevation in GH receptor and serum GH binding protein in the mouse.Endocrinology 126, 1270–5.PubMedGoogle Scholar
  34. Shumaker, R.C. (1986) PKCALC: A basic interactive computer program for statistical and pharmakinetic analysis of data.Drug Metab. Rev. 17, 332–48.Google Scholar
  35. Sinha, Y.N., Selby, F.W., Lewis, U.J. and Vanderlaan, W.P. (1972) Studies of GH secretion in mice by a homologous radioimmunoassay for mouse GH.Endocrinology 91, 784–92.PubMedGoogle Scholar
  36. Sinha, Y.N., Salocks, C.B. and Vanderlaan, W.P. (1975) Prolactin and growth hormone levels in different inbred strains of mice: Patterns in association with estrous cycle, time of day, and perhenazine stimulation.Endocrinology 97, 1112–22.PubMedGoogle Scholar
  37. Smith, W.C. and Talamantes, F. (1988) Gestational profile and affinity cross-linking of the mouse serum growth hormone binding protein.Endocrinology 123, 1489–94.PubMedGoogle Scholar
  38. Smith, W.C., Kumiyoshi, J. and Talamantes, F. (1989) Mouse serum growth hormone (GH) binding protein has GH receptor extracellular and substituted transmembrane domains.Mol. Endocrinol. 3, 984–90.PubMedGoogle Scholar
  39. Turyn, D. and Dellacha, J.M. (1978) Specific binding of iodinated growth hormone to rat liver ‘in vivo’.Endocrinology 103, 1190–95.PubMedGoogle Scholar
  40. Wagner, T.E., Hoppe, P.C., Jollick, J.D., Scholl, D.R., Hodinka, R.L. and Gault, J.B. (1981) Microinjection of a rabbit \-globin gene into zygotes and its subsequent expression in adult mice and their offspring.Proc. Natl Acad. Sci. USA 78, 6376–80.PubMedGoogle Scholar
  41. Wallace, A.L.C. and Stacy, B.D. (1975) Disappearance of125Ilabelled rat growth hormone in nephrectomized and sham operated rats.Horm. Metab. Res. 7, 135–8.Google Scholar
  42. Wallace, A.L.C., Stacy, B.D. and Thorburn, G.D. (1972) The fate of radioiodinated sheep growth hormone in intact and nephrectomized sheep.Pfluegers Arch. 331, 25–7.CrossRefGoogle Scholar

Copyright information

© Chapman & Hall 1993

Authors and Affiliations

  • D. Turyn
    • 1
  • A. Bartke
    • 2
  1. 1.Facultad de Farmacia y Bioquimica Junin 956Instituto de Quimica y Fisicoquimica Biológicas (UBA-CONICET)Buenos AiresArgentina
  2. 2.Department of PhysiologySouthern Illinois University School of MedicineCarbondaleUSA

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