Whatever Happened to Urogastrone?

Abstract

It has long been recognised that in pregnancy the symptoms of peptic ulcer often diminish and that the clinical association of active peptic ulceration and pregnancy is unusual. Sandweiss et al. [1] in 1938 showed that hormones could heal peptic ulcers in dogs. Dogs subjected to an ulcer producing Mann-Williamson type of gastric procedure healed their ulcers when injected with an anterior pituitary like hormone (Antuitrin S.). It was therefore suggested that a hormone produced in pregnancy might encourage ulcer healing. Culmer and Atkinson [2] also showed that anterior pituitary-like sex hormones which were extracted from human pregnancy urine produced significant gastric hyposecretion in dogs. It was suggested that the gastric secretory inhibiting agent was enterogastrone and because it was excreted in the urine it was called 'urogastrone'. Was it this agent that healed ulcers in pregnancy? In 1975 Gregory working at ICI in the United Kingdom identified the structure of this substance isolated from human urine [3]. His group subsequently showed that it was not only a potent inhibitor of gastric acid secretion but that it had a mucosal effect on gastric mucosal cells also. The predictions made for urogastrone in 1938 were thus found to be true. The story however begins rather than ends at this point. In 1962 Cohen [4] had isolated from the submandibular glands of the mouse a protein which could cause incisor tooth eruption and premature eyelid opening in newborn animals. Cohen had actually been looking for nerve growth promoting material in mouse submandibular glands and this new finding was an unexpected one. The structure of the material isolated by Gregory (urogastrone) and that isolated by Cohen which was subsequently known as epithelial growth factor (EGF) were then shown to be identical, and indeed the polypeptide is now often given the conjoint name urogastrone/EGF. Epithelial growth factor circulates in the blood and body fluids of man and animals. There is some disagreement concerning its molecular size in these situations. EGF itself is a polypeptide of mass 6000 containing 53 amino acids. Three disulphide groups bind various parts of the peptide chain together. It seems likely that it is secreted as a large molecule attached to an EGFbinding protein. The binding protein has proteolytic activity and consequently produces smaller EGF molecules [5]. Using chromatography it has been possible to show that there are in fact two epithelial growth factors (I and II). One of these lacks a terminal asparagine group. The physiological role of EGF II is unknown [6]. In human sera the mass of transported EGF was found to be 200 000 but gastric juice and saliva contained smaller molecules [7]. This is in keeping with the known occurrence of biologically active peptides in multiple forms in tissue fluids. There is no disagreement concerning the tissues which contain EGF in man and animals. The major tissues in which it occurs are the submandibular glands, Brunner's glands in the