Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6

• Published in: Pflügers Archiv Vol. 465; no. 11; p. 1613
• Main Authors: Lameris, A L L, Hess, M W, van Kruijsbergen, I, Hoenderop, J G J, Bindels, R J M
• Format: Journal Article
• Language: English
• Published: Germany 01.11.2013
• Subjects: Animals; Colon - drug effects; Colon - metabolism; H(+)-K(+)-Exchanging ATPase - genetics; H(+)-K(+)-Exchanging ATPase - metabolism; Homeostasis; Intestinal Absorption - drug effects; Magnesium - blood; Magnesium - metabolism; Magnesium - urine; Mice; Mice, Inbred C57BL; Omeprazole - pharmacology; Proton Pump Inhibitors - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription, Genetic; TRPM Cation Channels - genetics; TRPM Cation Channels - metabolism
• ISSN: 1432-2013
• DOI: 10.1007/s00424-013-1306-0

Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, used by millions of patients suffering from gastric acid-related complaints. Although PPIs have an excellent safety profile, an increasing number of case reports describe patients with severe hypomagnesemia due to long-term PPI use. As there is no evidence of a renal Mg²⁺ leak, PPI-induced hypomagnesemia is hypothesized to result from intestinal malabsorption of Mg²⁺. The aim of this study was to investigate the effect of PPIs on Mg ²⁺homeostasis in an in vivo mouse model. To this end, C57BL/6J mice were treated with omeprazole, under normal and low dietary Mg²⁺ availability. Omeprazole did not induce changes in serum Mg²⁺ levels (1.48 ± 0.05 and 1.54 ± 0.05 mmol/L in omeprazole-treated and control mice, respectively), urinary Mg²⁺ excretion (35 ± 3 μmol/24 h and 30 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively), or fecal Mg²⁺ excretion (84 ± 4 μmol/24 h and 76 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively) under any of the tested experimental conditions. However, omeprazole treatment did increase the mRNA expression level of the transient receptor potential melastatin 6 (TRPM6), the predominant intestinal Mg²⁺ channel, in the colon (167 ± 15 and 100 ± 7 % in omeprazole-treated and control mice, respectively, P < 0.05). In addition, the expression of the colonic H⁺,K⁺-ATPase (cHK-α), a homolog of the gastric H⁺,K⁺-ATPase that is the primary target of omeprazole, was also significantly increased (354 ± 43 and 100 ± 24 % in omeprazole-treated and control mice, respectively, P < 0.05). The expression levels of other magnesiotropic genes remained unchanged. Based on these findings, we hypothesize that omeprazole inhibits cHK-α activity, resulting in reduced extrusion of protons into the large intestine. Since TRPM6-mediated Mg²⁺absorption is stimulated by extracellular protons, this would diminish the rate of intestinal Mg²⁺ absorption. The increase of TRPM6 expression in the colon may compensate for the reduced TRPM6 currents, thereby normalizing intestinal Mg²⁺ absorption during omeprazole treatment in C57BL/6J mice, explaining unchanged serum, urine, and fecal Mg²⁺ levels.