title: Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6.
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.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: A L L
authors.initials: AL
authors.lastname: Lameris
authors.forename: M W
authors.initials: MW
authors.lastname: Hess
authors.forename: I
authors.initials: I
authors.lastname: van Kruijsbergen
authors.forename: J G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: R J M
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007408:Intestinal Absorption / Q000187:drug effects; D008274:Magnesium / Q000097:blood / Q000378:metabolism / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D009853:Omeprazole / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D050053:TRPM Cation Channels; C530168:Trpm6 protein, mouse; D017506:H(+)-K(+)-Exchanging ATPase; D008274:Magnesium; D009853:Omeprazole