Pharmacokinetics of radioiodinated human and ovine growth hormones in transgenic mice expressing bovine growth hormone
- 45 Downloads
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.
KeywordsGH receptors PRL receptors transgenic mice
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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