Histamine metabolism of gastric carcinoids in Mastomys natalensis.
Pharmacological inhibition of gastric acid secretion and subsequent hypergastrinemia in Mastomys natalensis is an experimental model well suited for the study of gastric carcinoid formation. The genetic susceptibility of Mastomys to develop such tumors is a feature reminiscent of the situation in patients with the MEN-1 Zollinger Ellison syndrome, in whom tumor-induced hypergastrinemia, promotes the development of gastric carcinoids. Chronic hypergastrinemia, induced by the irreversible H2-receptor antagonist loxtidine will cause carcinoid formation in Mastomys already after four to six months. As in humans, gastric carcinoids in Mastomys are mainly composed of enterochromaffinlike (ECL) cells and have low malignant potential. Administration of exogenous gastrin to normal young animals increases the expression of histidine decarboxylase (HDC) mRNA in the oxyntic mucosa within 30 minutes. Endogenous hypergastrinemia, induced by short-time loxtidine treatment (three to 29 days) enhances the expression of HDC mRNA, histamine contents and ECL cell numbers in the oxyntic mucosa. Long-term loxtidine treatment (seven to 21 months) results in sustained hypergastrinemia and tumor formation. Tumor-bearing animals exhibited an increase in HDC mRNA and histamine content in the oxyntic mucosa as well as increased urinary excretion of the main histamine metabolite, tele-methylimidazole acetic acid (MeImAA). Subsequent to cessation of loxtidine treatment for two weeks, all parameters of histamine metabolism were normalized in tumor-bearing animals. These results indicate that gastric carcinoids developing during hypergastrinemia are well-differentiated neoplasms whose histamine synthesis and metabolism is regulated by plasma gastrin.
Kölby
L
L
Department of Surgery, Sahlgrenska University Hospital, Göteborg, Sweden.
Wängberg
B
B
Ahlman
H
H
Modlin
I M
IM
Nilsson
O
O
D000818:Animals; D002276:Carcinoid Tumor / Q000139:chemically induced / Q000378:metabolism*; D004195:Disease Models, Animal; D019861:Enterochromaffin-like Cells / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D005755:Gastrins / Q000009:adverse effects / Q000097:blood*; D006632:Histamine / Q000378:metabolism*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000187:drug effects / Q000235:genetics; D009115:Muridae; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
D005755:Gastrins; D006635:Histamine H2 Antagonists; D014230:Triazoles; C039993:loxtidine; D006632:Histamine; D006640:Histidine Decarboxylase