Evidence for a regulatory role for histamine in gastric enterochromaffin-like cell proliferation induced by hypergastrinemia.
OBJECTIVE
Hypergastrinemia, induced by sustained suppression of gastric acid secretion, is associated with gastric enterochromaffin-like (ECL) cell hyperplasia and carcinoid tumor formation. We examined the effect of a selective H1-histamine antagonist, terfenadine, on gastric mucosal cell proliferation to determine whether histamine might modulate ECL cell generation.


METHODS
The rodent mastomys received the H2-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days. Controls received water or terfenadine alone. Serum gastrin levels and tissue histamine content were assayed by radioimmunoassays, and tissue chromogranin levels determined (Western blot analysis). In vivo cell proliferation was measured by bromodeoxyuridine (BrdU, 200 mg/kg/day, 3 days) incorporation. Gastric mucosal thickness was determined, ECL cell number was assessed, and the percentage of proliferating ECL cells quantitated. To evaluate the direct action on ECL cells we then studied the effect of terfenadine on histamine secretion and DNA synthesis (BrdU uptake) in an isolated preparation (approximately 90% pure) of ECL cells.


RESULTS
Loxtidine increased serum gastrin levels, mucosal thickness, tissue chromogranin levels, tissue histamine content, BrdU incorporation, ECL cell number, and proliferating ECL cells (all parameters p < 0.05). Terfenadine alone, irrespective of dosage, had no significant effect. The high dose in combination with loxtidine significantly inhibited the increase in tissue chromogranin levels, tissue histamine content, ECL cell number and proliferating ECL cells (p < 0.05), but did not alter other parameters, compared to loxtidine alone. The low does did not alter the loxtidine-induced changes. In pure isolated ECL cells, terfenadine did not alter histamine secretion either alone or in combination with gastrin (10 nM). DNA synthesis was significantly inhibited by terfenadine (IC50 10(-10) M).


CONCLUSIONS
Terfenadine specifically inhibited the effect of loxtidine-induced ECL cell proliferation in vivo and significantly inhibited ECL cell DNA synthesis in vitro. We postulate that histamine, through an H1 receptor, positively modulates gastric ECL cell proliferation.
Modlin
I M
IM
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
Zhu
Z
Z
Tang
L H
LH
Kidd
M
M
Lawton
G P
GP
Miu
K
K
Powers
R E
RE
Goldenring
J R
JR
Pasikhov
D
D
Soroka
C J
CJ
D000818:Animals; D002455:Cell Division; D002864:Chromogranins / Q000032:analysis; D004247:DNA / Q000096:biosynthesis; D004759:Enterochromaffin Cells / Q000166:cytology*; D005260:Female; D005753:Gastric Mucosa / Q000166:cytology*; D005755:Gastrins / Q000097:blood*; D006632:Histamine / Q000502:physiology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006965:Hyperplasia; D066298:In Vitro Techniques; D008297:Male; D009115:Muridae; D016593:Terfenadine / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D002864:Chromogranins; D005755:Gastrins; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D014230:Triazoles; C039993:loxtidine; D016593:Terfenadine; D006632:Histamine; D004247:DNA