Omeprazole enhances the colonic expression of the Mg2+ 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.

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

“…Impaired intestinal magnesium absorption, rather than renal absorption, seems to mediate the effect of proton pump inhibitors. Potential mediators include increased intestinal magnesium secretion, decreased active transcellular magnesium absorption due to decreased TRPM6 activity secondary to decreased intestinal acidity, or decreased paracellular magnesium absorption (77,78).…”

Magnesium in Man: Implications for Health and Disease

“…Intestinal expression of TRPM6 is located in cecum and colon (196,300). In a study with rat colon epithelium, 37% of Mg 2ϩ was transported transcellularly (272).…”

“…Although most studies do not report hypomagnesemia in patients being treated with thiazide diuretics, some patient groups may be at risk (101). Patients with low initial Mg 2ϩ values, such as elderly patients or patients with chronic heart failure, may develop hypomagnesemia after chronic thiazide treatment (238,285 (300). Therefore, it was hypothesized that omeprazole may inhibit the activity of the colonic H ϩ -K ϩ -ATPase, resulting in reduced extrusion of protons into the colon.…”

“…Therefore, it was hypothesized that omeprazole may inhibit the activity of the colonic H ϩ -K ϩ -ATPase, resulting in reduced extrusion of protons into the colon. Since TRPM6 activity increases at lower external pH, decreased proton secretion may reduce TRPM6 activity, for which increased TRPM6 expression may compensate (300,313). However, increased TRPM6 expression may not be sufficient to prevent malabsorption of Mg 2ϩ in colon in all patients.…”

Gastric Acid-Dependent Diseases: A Twentieth-Century Revolution

“…Some adverse effects of PPIs include hypocalcaemia in elderly patients undergoing chronic therapy [45]. A very small number of patients may develop hypomagnesaemia with serious effects on the central nervous, cardiac, and musculoskeletal systems [46], possibly due to a mutation in the duodenal Mg transporters enhancing their susceptibility to activated PPIs in the duodenum [47]. On the whole, however, given their relatively minor adverse effects discovered only after millions of patient-years of experience, and their unceasing and potent effectiveness, which has revolutionized the treatment of acid-peptic foregut disease, these drugs have a remarkably low risk/benefit.…”