Oral administration of
BL-6341 hydrochloride, a long-acting
histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromaffin-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse
hyperplasia, focal adenomatous
hyperplasia, and
carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL cell
hyperplasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound,
cimetidine (950 mg/kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of
BL-6341. Dose-related elevations of serum
gastrin were observed with
BL-6341, while
cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of
BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of
acid secretion, which is the negative feedback mechanism controlling the production of
gastrin. Only the 300 mg/kg dose of
BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and
carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell
carcinoid neoplasia. All genetic toxicology tests performed with
BL-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of
tumorigenesis.