Omeprazole Enhances the Colonic Expression of the Mg(2+) Transporter TRPM6

Pflugers Arch. 2013 Nov;465(11):1613-20. doi: 10.1007/s00424-013-1306-0. Epub 2013 Jun 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*
  • Transcription, Genetic

Substances

  • Proton Pump Inhibitors
  • RNA, Messenger
  • TRPM Cation Channels
  • Trpm6 protein, mouse
  • H(+)-K(+)-Exchanging ATPase
  • Magnesium
  • Omeprazole