Human transforming growth factor alpha (TGF-alpha) is digested to a smaller (1-43), less biologically active, form in acidic gastric juice.
BACKGROUND
Transforming growth factor alpha (TGF-alpha) is a 50 amino acid peptide with potent proliferative and cytoprotective activity present in gastric mucosa and juice.


OBJECTIVE
To determine the forms and biological activity of natural and recombinant TGF-alpha following incubation with acid pepsin.


METHODS
Human gastric juice was obtained under basal conditions from patients taking acid suppressants and from volunteers undergoing intragastric neutralisation.


METHODS
Samples were analysed using mass spectroscopy and/or high pressure liquid chromatography with radioimmunoassay. Biological activity was determined using thymidine incorporation into rat hepatocytes and an indomethacin/restraint induced gastric damage rat model.


RESULTS
TGF-alpha(1-50) is cleaved to TGF-alpha(1-43) by acid pepsin and this is the predominant form in normal gastric juice. However, intragastric neutralisation or taking acid suppressants caused the predominant form to be TGF-alpha(1-50). TGF-alpha(1-43) had only half of the ability to maximally stimulate [(3)H]thymidine incorporation into primary rat hepatocytes (28 177 (1130) DPM/well for 2.16 nM TGF-alpha(1-43) v 63 184 (3536) DPM/well for TGF-alpha(1-50); p<0.001). A similar reduced potency was seen when used in an indomethacin induced rat gastric damage model (0.18 micro mol/kg/h of TGF-alpha(1-43) reduced ulcer area by 19% whereas TGF-alpha(1-50) reduced area by 62%; p<0.001).


CONCLUSIONS
TGF-alpha(1-50) is cleaved to the TGF-alpha(1-43) form by acid pepsin, causing 2-5-fold loss of biological activity. Such changes may have relevance to the actions of acid suppressants and the importance of this peptide in both normal and abnormal growth.
Marchbank
T
T
Imperial College Faculty of Medicine, Department of Gastroenterology, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Boulton
R
R
Hansen
H
H
Playford
R J
RJ
D000818:Animals; D001681:Biological Assay; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004063:Digestion; D005750:Gastric Juice / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007213:Indomethacin; D013058:Mass Spectrometry; D023421:Models, Animal; D010434:Pepsin A / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D011863:Radioimmunoassay; D011897:Random Allocation; D051381:Rats; D013270:Stomach / Q000187:drug effects; D016211:Transforming Growth Factor alpha / Q000737:chemistry / Q000378:metabolism*
D010446:Peptide Fragments; D020033:Protein Isoforms; D016211:Transforming Growth Factor alpha; D010434:Pepsin A; D007213:Indomethacin