Ferric Citrate Hydrate Has Little Impact on Hyperplasia of Enterochromaffin Cells in the Rat Small Intestine Compared to Sodium Ferrous Citrate

Abstract

Introduction: The most detrimental factor preventing the use of oral iron in the treatment of iron deficiency anemia is gastrointestinal side effects accompanied by nausea and vomiting. Anorexia is a known secondary effect of nausea and vomiting. The important gastrointestinal signaling molecule 5-hydroxytryptamine (5-HT) is critically involved in not only physiological function but also nausea and vomiting. The present study was designed to compare the effects of the administration of sodium ferrous citrate (SF) and ferric citrate hydrate (FC) to rats on anorexia and hyperplasia of enterochromaffin cells, which mainly synthesize and store 5-HT.

Methods: Rats received either SF (3 or 30 mg/kg/day) or FC (30 mg/kg/day) orally for 4 days. Food and water intakes were measured every 24 h during the study. At 96 h after the first administration of the oral iron preparation, the duodenal and jejunal tissues were collected for analysis. Enterochromaffin cells were detected by immunohistochemical analysis.

Results: Administration of 3 mg/kg SF had no effect on anorexia but led to increased hyperplasia of enterochromaffin cells in the duodenum (p < 0.1). Administration of 30 mg/kg SF significantly decreased food and water intakes and significantly increased hyperplasia of enterochromaffin cells in the duodenum and jejunum. Alternatively, administration of 30 mg/kg FC had no significant effect on food and water intakes or hyperplasia of enterochromaffin cells.

Conclusion: The lower impact on the hyperplasia of enterochromaffin cells of FC compared to SF may contribute to the maintenance of rats' physical condition.

Keywords: Anorexia; Enterochromaffin cells; Ferric citrate hydrate; Sodium ferrous citrate; Tryptophan hydroxylase.

Fig. 1

Effects of SF on food and water intakes. After the first administration of either 3 mg/kg SF (a, c) or 30 mg/kg SF (b, d), food (a, b), and water (c, d) intakes were measured every 24 h up to 96 h. Each column represents the mean ± SE (a, c, n = 8; b, d, n = 6). **p < 0.01 versus control; ^†††p < 0.001, ^††p < 0.01, ^†p < 0.05 versus 0 h.

Fig. 2

Effects of 3 mg/kg SF on TPH and substance P expression in rat duodenal and jejunal tissue. Duodenal (a, e) and jejunal (b, f) tissues were dissected and fixed with 4% paraformaldehyde for immunohistochemical examination with either anti-TPH antibody (a, b) or anti-substance P antibody (e, f). Scale bar, 100 μm. Magnified view of the region indicated by the dotted square in each photograph. c, d, g, and h Show the numbers of either anti-TPH or anti-substance P antibody-positive cells expressing either TPH or substance P in the mucosa (arrows in a, b, e, and f, respectively). Each column represents the mean ± SE (n = 8).

Fig. 3

Effects of 30 mg/kg SF on TPH and substance P expression in rat duodenal and jejunal tissue. Duodenal (a, e) and jejunal (b, f) tissues were dissected and fixed with 4% paraformaldehyde for immunohistochemical examination with either anti-TPH antibody (a, b) or anti-substance P antibody (e, f). Scale bar, 100 μm. Magnified view of the region indicated by the dotted square in each photograph. c, d, g, and h Show the numbers of either anti-TPH or anti-substance P antibody-positive cells expressing either TPH or substance P in the mucosa (arrows in a, b, e, and f, respectively). Each column represents the mean ± SE (n = 12). ***p < 0.001, *p < 0.05 versus control.

Fig. 4

Effects of 30 mg/kg FC on food and water intake. After the first administration of 30 mg/kg SF, food (a) and water (b) intake were measured every 24 h up to 96 h. Each column represents the mean ± SE (n = 9).

Fig. 5

Effects of 30 mg/kg FC on TPH and substance P expression in rat duodenal and jejunal tissue. Duodenal (a, e) and jejunal (b, f) tissues were dissected and fixed with 4% paraformaldehyde for immunohistochemical examination with either anti-TPH antibody (a, b) or anti-substance P antibody (e, f). Scale bar, 100 μm. Magnified view of the region indicated by the dotted square in each photograph. c, d, g, and h Show the numbers of either anti-TPH or anti-substance P antibody-positive cells expressing either TPH or substance P in the mucosa (arrows in a, b, e, and f, respectively). Each column represents the mean ± SE (n = 9).

Fig. 6

Possible mechanisms underlying the nausea and vomiting induced by iron preparations. SP, substance P; 5-HT, 5-hydroxytryptamine; DMT1, divalent metal transporter 1; DcytB, duodenal cytochrome B.