Distribution of i.v. administered epidermal growth factor in the rat

doi:10.1016/0167-0115(88)90024-9

Regulatory Peptides

Volume 23, Issue 2, November 1988, Pages 161-169

https://doi.org/10.1016/0167-0115(88)90024-9 Get rights and content

Abstract

The distribution of i.v. injected ¹²⁵I-labeled epidermal growth factor (EGF) was examined in the rat. The uptake of radioactivity was examined for the following tissues: liver, kidney, skin, stomach, small intestine, colon, brain, submandibular gland, lung, spleen, and testis. ¹²⁵I-EGF was cleared from the circulation within minutes. At 2.5 min after the injection only 7% of the label was left in the blood. Most of the label was found in the liver (52%), the kidneys (14%), the small intestine (11%) and the skin (7%). The other organs examined contained 1% or less of the radioactivity. The uptake of ¹²⁵I-EGF per g tissue was markedly higher for the liver and kidneys than for the rest of the organs. By autoradiography ¹²⁵I-EGF was found in the peripheral parts of the classical liver lobule, in the proximal tubules of the kidneys, in the surface epithelium of the stomach, and in the surface epithelium of the villi in the small intestine. In conclusion the present study showed that small doses of homologous EGF was cleared from the circulation of rats within minutes, mainly by the liver, the kidneys, and the small intestine.

References (25)

H. Gregory et al.
The identification of urogastrone in serum, saliva, and gastric juice
Gastroenterology
(1979)
A.P. Savage et al.
Epidermal growth factor in blood
Regul. Pept.
(1986)
S. Cohen
Isolation of a mouse submaxillary gland protein accelerating incisor cruption and cylid opening in the newborn animal
J. Biol. Chem.
(1962)
E. Nexø et al.
Purification of human epidermal growth factor-urogastrone by immunoaffinity chromatography
S.E. Raper et al.
Translocation of epidermal growth factor to the hepatocyte nuclcus during rat liver regeneration
Gastroenterology
(1987)
J.A. Walker-Smith et al.
Intravenous epidermal growth factor/urogastrone increases small-intestinal cell proliferation in congenital microvillous atrophy
Lancet
(1985)
P. Skov Olsen et al.
Quantitation of epidermal growth factor in the rat. Identification and partial characterization of duodenal EGF
Scand. J. Gastroenterol.
(1983)
R.A. Goodlad et al.
Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats
Gut
(1987)
M.D. Hollenberg
Epidermal growth factor-urogastrone, a polypeptide acquiring hormonal status
Vitamins Hormones
(1979)
R.J. St. Hilaire et al.
Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system

E. Draghi et al.

The stimulation by epidermal growth factor (urogastrone) of the growth of neonatal rat hepatocytes in primary tissue culture and its modulation by serum and associated pancreatic hormones

J. Cell Physiol.

(1980)

Skov Olsen, P., Boesby, S., Kirkegaard, P., Therkelsen, K., Poulsen, S.S. and Nexø, E., Influence of epidermal growth...

Cited by (54)

Epidermal growth factor and insulin-like growth factor I upregulate the expression of the epidermal growth factor system in rat liver
2000, Journal of Hepatology
Background/Aim: Both epidermal growth factor and insulin-like growth factor I play a role in connection with the liver. In the present study, the possible interaction of these two growth factor systems was studied by investigating the effect of epidermal growth factor or insulin-like growth factor I treatment on the expression of the epidermal growth factor receptor, and its activating ligands, transforming growth factor-α and epidermal growth factor.
Methods: Fifty-five male rats received no treatment, human recombinant epidermal growth factor or human recombinant insulin-like growth factor I for either 3 or 7 days. The amount of epidermal growth factor receptor, transforming growth factor-α, and epidermal growth factor mRNA was quantitated by a calibrated user-friendly RT-PCR assay (CURT-PCR), and the expression of transforming growth factor-α and epidermal growth factor peptides was quantitated by ELISA.
Results: Control liver (n=16) contained a mean (±SD) value of 12.7±7.4×10⁻¹⁸ mol epidermal growth factor receptor mRNA, 3.8±2.0×10⁻¹⁸ mol transforming growth factor-α mRNA and 0.8±0.4×10⁻¹⁸ mol epidermal growth factor mRNA per μg total RNA and 9.8±1.6 fmol/mg protein epidermal growth factor and 144±22 fmol/mg protein transforming growth factor-α. Both epidermal growth factor and insulin-like growth factor I treatment increased the expression of mRNA for transforming growth factor-α and epidermal growth factor receptor, as well as the expression of transforming growth factor-α peptide. The level of epidermal growth factor receptor and transforming growth factor-α mRNA expression was found to correlate both in control and growth factor-treated animals, whereas the expression of epidermal growth factor receptor and epidermal growth factor showed no correlation. Marked differences were seen upon activation of the two growth factor systems, as epidermal growth factor, but not insulin-like growth factor I treatment, increased the plasma concentration of urea and decreased the concentration of insulin-like growth factor I and the liver enzymes, alanine aminotransferase and alkaline phosphatase.
Conclusion: Our results show that epidermal growth factor and insulin-like growth factor I, which belong to two different growth factor systems, both induce a correlated upregulation of transforming growth factor-α and epidermal growth factor receptor mRNA in rat liver. Although marked differences were observed after treatment with either epidermal growth factor or insulin-like growth factor I on the liver as reflected in the plasma concentrations of e.g. liver enzymes, a common motif in their action involves an upregulation of the expression of the epidermal growth factor system.
Time-dependent changes of levels of endogenous epidermal growth factor in submandibular glands, in kidneys, and in urine in rats during systemic treatment with EGF
1998, Regulatory Peptides
Background: Exogenous EGF influences the levels of endogenous EGF differently in the submandibular glands (SMG) and the kidneys. The aim of the present study was to examine the time-dependent changes in levels of endogenous EGF during 1–4 weeks of EGF treatment. Methods: Female rats were allocated into five groups receiving EGF subcutaneously (150 μg/kg/day) for 0 (controls), 1, 2, 3 and 4 weeks prior to sacrifice at an age of 12 weeks. At the end of the study period, 24-h urine samples were collected. Results: The weight of the SMG increased during EGF treatment (303±33 (controls), 359±37 (1 week EGF, P<0.01), 390±30 (4 weeks EGF, P<0.001) (mg mean±S.D.)). The EGF content of the SMG was unchanged after 1 week but threefold decreased after 4 weeks of treatment, respectively. The expression of EGF mRNA was decreased after 1 and 4 weeks as assessed with in situ hybridization. The weight of the kidneys was unchanged after 1 week and increased after 4 weeks of treatment (828±105 mg (controls) vs. 935±44 mg (4 weeks EGF, P<0.005)). The renal content and the urinary excretion of EGF were significantly increased by 20–30% only in the group treated for 4 weeks. Conclusion: EGF treatment induces a time-dependent decrease in the EGF content in the SMG most likely by reducing the biosynthesis of endogenous EGF. In contrast, the EGF content in kidneys and in urine was unchanged after 1 week and increased after prolonged treatment.
Perturbation of epidermal growth factor clearance after radioiodination and its implications
1997, Journal of Pharmaceutical Sciences
The clearance of human epidermal growth factor (hEGF1–53) has been thought to be mediated mainly by a high-capacity receptor system, yet relatively low in vivo clearance rates (< 10 mL/min/kg) and long terminal elimination half-lives (> 120 min) have been observed in rats receiving the peptide that was iodinated by the oxidative chloramine-T (CT) method. We investigated if a mild, less oxidative iodination by the lactoperoxidase (Enzymobeads, EB) method, which is known to yield an iodinated peptide with receptor-binding equivalence, could produce a labeled peptide that behaves pharmacokinetically similar to the native material. For comparison, a parallel study was also conducted with EB-¹²⁵I-hEGF1–48, which in its native form has a much reduced receptor binding activity due to the loss of the C-terminal pentapeptide. Plasma radioactivity concentrations were determined by trichloroacetic acid (TCA) precipitation and immunoprecipitation. Rats cleared unlabeled hEGF1–53 and hEGF1–48 markedly faster (CL_tot > 120 mL/min/kg) than their radiolabeled counterparts. Approximately 96% of the hEGF1–53 dose was cleared during the initial phase (0–4 min), as opposed to only 5–14% for the iodinated peptide. Similar change was also observed for EB-¹²⁵I-hEGF1–48 and CT-¹²⁵I-hEGF1–53. The pharmacokinetic behavior of EB-¹²⁵I-hEGF1–53 was, in fact, comparable to that of CT-¹²⁵I-hEGF1–53. These observations indicate that receptor-binding equivalence does not have direct relationship with in vivo EGF clearance. Both iodination methods (oxidative CT and less oxidative EB) might have perturbed one or more steps in the cascade of ligand–receptor internalization and intracellular procession, which in turn modified the disposition of the peptides. In addition, the two independent precipitation techniques for the same peptide generated different kinetic outcomes. The overall experimental results suggest that it is unacceptable to use an iodinated form to characterize the disposition of peptides/proteins like EGF with a specific receptor system mediating its clearance.
The effects of chronic administration of epidermal growth factor (EGF) to rats on the levels of endogenous EGF in the submandibular glands and kidneys
1996, Regulatory Peptides
Epidermal growth factor (EGF) is mainly produced in the submandibular glands (SMG) and in the kidneys. It has recently been reported that EGF-related ligands may induce their own biosynthesis (autoinduction) in vitro. In the present paper, we investigated whether chronic systemic treatment with EGF influenced the amount of endogenous EGF in the SMG and kidneys. Eight-week-old female Wistar rats were treated with subcutaneous injections of placebo (n = 16) or human recombinant EGF (150 μg/kg per day, n = 8) for 4 weeks. Urine was sampled the last 24 h of the study period. At the time of killing, the SMG and kidneys were removed. The SMG was larger in the EGF-treated animals, 229.8 ± 35.5 (mean ± SD) mg than in the control animals, 181.7 ± 18.1 mg (P < 0.01). The total EGF content was smaller (0.51 ± 0.15 vs. 1.12 ± 0.40 nmol EGF/SMG, P < 0.001). The kidneys were larger in the EGF-treated animals (1.38 ± 0.08 vs. 1.28 ± 0.08 g, P < 0.05), but the EGF content and urinary excretions were not changed. In conclusion, chronic systemic treatment with EGF causes growth of the SMG with concomitantly reduced contents of EGF, and growth of the kidneys with unchanged content and excretion of EGF. These findings suggest that EGF may play a part in the regulation of the growth of the SMG and in EGF biosynthesis.
Pharmacokinetic, metabolic, and antidiarrheal properties of (d and l) heptapeptides of sorbin in rodent
1995, Peptides
The C-terminal heptapeptide-amide (C7-sorbin) is the minimal biologically active fragment of sorbin inducing an increase in intestinal hydroelectrolytic absorption. An analogue (D7-sorbin), characterized by the replacement of the ultimate C-terminal amino acid l-alanine-amide by d-alanine-amide, was synthetized. For pharmacokinetic studies, D7-sorbin and C7-sorbin were tritium labeled. After IV injection, clearances were 10.6 and 30.2 ml⁻¹ for D7-sorbin and C7-sorbin, respectively, and MRT were 34 and 18 min. After SC administration, C_max attained 0.41% and 0.12% of the dose/ml, respectively. The IP route showed a 45-min delay before C_max and a 100% bioavailability for both peptides. D7-sorbin was principally excreted in urine, as shown by balance study, and in part in intact form, as controlled by mass spectrometry. D7-sorbin induced a significant decrease of the VIP-induced ileal secretion, previously observed with C7-sorbin. The change of l-Ala to d-Ala increased the stability of the synthetic C-terminal peptide of sorbin whereas its biological activity, bioavailability, and route of elimination were unchanged.
Effect of epidermal growth factor treatment and polychlorinated biphenyl exposure in a dietary-exposure mouse model of steatohepatitis
2021, Environmental Health Perspectives

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Distribution of i.v. administered epidermal growth factor in the rat

Abstract

Gastroenterology

Regul. Pept.

J. Biol. Chem.

Gastroenterology

Lancet

Quantitation of epidermal growth factor in the rat. Identification and partial characterization of duodenal EGF

Scand. J. Gastroenterol.

Intravenous but not intragastric urogastrone-EGF is trophic to the intestine of parenterally fed rats

Gut

Epidermal growth factor-urogastrone, a polypeptide acquiring hormonal status

Vitamins Hormones

Hepatic sequestration and biliary secretion of epidermal growth factor: evidence for a high-capacity uptake system

The stimulation by epidermal growth factor (urogastrone) of the growth of neonatal rat hepatocytes in primary tissue culture and its modulation by serum and associated pancreatic hormones

J. Cell Physiol.