Gastric Enterochromaffin-Like Cell Hyperplasia and Neoplasia in the Rat: An Indirect Effect of the Histamine H₂-Receptor Antagonist, BL-6341

Abstract

Oral administration of BL-634 1 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 rng/kdday 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 celI hyperpIasia 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-634 1 , while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-634 1. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 rng/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-634 1 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis. INTRODU~IONThe toxicologic testing of new, potent, long-acting histamine H,-receptor antagonists and H+, K+-ATPase inhibitors has resulted in several types of proliferative gastric changes in chronic rat studies. The most noteworthy of these is the occurrence of gastric carcinoid tumors in the oxyntic mucosa (2, 18, 34). These proliferative endocrine changes are distinct from those produced by the gastric carcinogen, N-methyl-N-nitro-N-nitrosoguanidine (MNNG), that produces adenocarcinomas primarily in the pylonc region of the stomach (28). The histamine H,-blocker, tiotidine, has produced a dysplasiakarcinoma syndrome in rats that resembles the lesions associated with MNNG (38).This report describes the occurrence of proliferative, gastric, endocrine cell changes in the fundic stomach of rats administered the long-acting H,-antagonist, BL-6341 hydrochloride. It discusses the significance of these lesions, proposes a mechanism of tumorigenesis, and compares these observations with similar findings associated with other anti-secretagogues and those reported in man. METHODS Two-Year RatStudy. The carcinogenicity study was composed of 60 male and 60 female Charles R.iver, Sprague-pawley CD rats per dose group, and 110 male and 110 female negative controls. Rats were 8 weeks of age when the study was initiated.. They were administered ei...

Enterochromaffin-Like Cell Carcinoids in the Rat Gastric Mucosa following Long-Term Administration of Ranitidine

“…The frequency of carcinoids in the present study was similar to the frequency seen with omeprazole, 40 pmol/kg/day, in the 2-year studies, and corre lates with similar increases (~ 300%) in the levels of gastrin over the day. The time lapse between the induction of hypergastrinaemia and the development of both ECL-cell hyper plasia and carcinoids was also similar to that described previously [1,4,11], Such ECL-cell changes were not reported in the earlier long term study with ranitidine [13,14], but it would appear that the oxyntic mucosa was not stained specifically for ECL cells. ECLcell hyperplasia and carcinoids might there fore not have been recognized although areas or foci of nodular hyperplasia of the glandu lar stomach were reported [13].…”

Role of Persistent, Non-Genotoxic Tissue Damage in Rodent Cancer and Relevance to Humans

“…The induction of carcinoid tumors in rats and mice by omeprazole and other H2-antagonists depends on the production of high levels of gastrin (104)(105)(106)(107), as discussed earlier. High levels of gastrin appear to have a similar effect in humans, since carcinoid tumors of the stomach are much more common in patients with pernicious anemia than in the general population (164).…”

“…These tumors have been induced in rats and mice by histamine Hz-receptor antagonists, such as omeprazole and oxmetidine, and by the hypolipidemic agent, ciprofibrate. These compounds also induce a sustained 3-4 fold increase in plasma gastrin and a suppression of HCI secretion in rodents (104)(105)(106)(107). Moreover, at doses not producing marked increases in plasma gastrin or enterochromaffinlike cell (ECL) hyperplasia, no tumors of the glandular stomach arose, whereas at higher doses both of these early effects and tumors occurred, thus indicating the existence of a threshold dose (104).…”

Twenty-four-month oral carcinogenicity study of ebrotidine in rats

“…These results were expected, in view of those obtained in previous studies [42,43], demonstrating that ebrotidine does not possess any hyperplastic effect on different endocrine cell populations from the gastric mucosa of mice and rats. Carcinogenic effects on the rodent gastric mucosa have focused the attention on the antiulcerous therapies in recent years, due to the risk inherent to unsurmountable or excessively powerful H 2 -antagonists [6,7,8,44], as well as proton pump inhibitors [5,45].…”

“…In these cases, carcinoids are found, which are completely formed by enterochromaffin-like cells-the cells responsible for the secretion of histamine. This proliferative response is not attributed to a carcinogenic effect of the gastric secretion inhibitors per se but to a trophic effect due to the hypergastrinemia that achlorhydria induces [6][7][8].…”