title: H2-receptor blockade induces peptide YY and enteroglucagon-secreting gastric carcinoids in mastomys.
abstract: Gastric carcinoid tumor formation has been reported with prolonged achlorhydria in both animals and human beings. The hypothesis in this study was that the ablation of parietal cell function in an animal (mastomys) genetically predisposed to gastric neuroendocrine neoplasia would promote and accelerate tumor formation. Loxtidine, an irreversible H2-receptor blocker, was administered at 1 mg/kg/day in drinking water for 4 months to young mastomys (n = 16). After 4 months of treatment, 14 of 16 animals had gastric carcinoids compared with 0 of 16 young control animals and 4 of 16 older control animals. Ultrastructurally, these tumors were characterized by the presence of neurosecretory granules. Serum gastrin levels were elevated (230 +/- 40 pmol/L) in loxtidine-treated animals compared with control animals (26 +/- 8 pmol/L) (p less than 0.05). In addition, both peptide YY (620 +/- 160 pmol/L) and enteroglucagon (500 +/- 147 pmol/L) were significantly elevated compared with control groups (p less than 0.05). Similarly, in tumor tissue, peptide YY (676 +/- 152 pmol/gm) and enteroglucagon (551 +/- 164 pmol/gm) were found in large quantities, whereas gastrin was undetectable. These observations provide substantial support for the possible pathophysiologic role of gut peptides, particularly gastrin, in the generation of endocrine neoplasia. The advent of endocrine tumors after inhibition of a gut secretory cell (parietal) may be of considerable significance in understanding the genesis of endocrine neoplasia. Whether the drug acts as a neoplastic promoter of enterochromaffin-like cells or the tumor development is related to elevation of peptides such as gastrin cannot be established in this study. Long-term H2-receptor blockade with new potent, irreversible agents as an alternative to surgery may have potential grave implications that require careful consideration.
authors.affiliation: Department of Surgery, Yale University School of Medicine, West Haven, Conn 06510.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bilchik
authors.forename: O
authors.initials: O
authors.lastname: Nilsson
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
authors.forename: J
authors.initials: J
authors.lastname: Sussman
authors.forename: K A
authors.initials: KA
authors.lastname: Zucker
authors.forename: T E
authors.initials: TE
authors.lastname: Adrian
mesh_terms: D000818:Animals; D002273:Carcinogens; D002276:Carcinoid Tumor / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D004763:Glucagon-Like Peptides / Q000378:metabolism*; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D006965:Hyperplasia; D009115:Muridae; D019894:Peptide YY; D010455:Peptides / Q000378:metabolism*; D012016:Reference Values; D013270:Stomach / Q000187:drug effects / Q000473:pathology*; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D005768:Gastrointestinal Hormones; D006634:Histamine H1 Antagonists; D010455:Peptides; D014230:Triazoles; D019894:Peptide YY; D004763:Glucagon-Like Peptides; C039993:loxtidine