Glutathione depleting drugs, antioxidants and intestinal calcium absorption

Abstract

Glutathione (GSH) is a tripeptide that constitutes one of the main intracellular reducing compounds. The normal content of GSH in the intestine is essential to optimize the intestinal Ca²⁺ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K₃, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca²⁺ absorption. The GSH depleting drugs switch the redox state towards an oxidant condition provoking oxidative/nitrosative stress and inflammation, which lead to apoptosis and/or autophagy of the enterocytes. Either the transcellular Ca²⁺ transport or the paracellular Ca²⁺ route are altered by GSH depleting drugs. The gene and/or protein expression of transporters involved in the transcellular Ca²⁺ pathway are decreased. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca²⁺ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca²⁺ transport caused by GSH depleting drugs. The use of any of these antioxidants to ameliorate the intestinal Ca²⁺ absorption under oxidant conditions associated with different pathologies in humans requires more investigation with regards to the safety, pharmacokinetics and pharmacodynamics of them.

Keywords: Glutathione; Transcellular and paracellular Ca²⁺pathways; DL-buthionine-S,R-sulfoximine; Fructose rich diet; Menadione; Sodium deoxycholate; Glutamine; Ursodeoxycholic acid; Melatonin; Quercetin; Naringin

Core tip: The normal content of glutathione (GSH) in the intestine is essential to optimize the intestinal Ca²⁺ absorption. The use of GSH depleting drugs such as DL-buthionine-S,R-sulfoximine, menadione or vitamin K₃, sodium deoxycholate or diets enriched in fructose, which induce several features of the metabolic syndrome, produce inhibition of the intestinal Ca²⁺ absorption. The flavonoids quercetin and naringin highly abrogate the inhibition of intestinal Ca²⁺ absorption, not only by restoration of the GSH levels in the intestine but also by their anti-apoptotic properties. Ursodeoxycholic acid, melatonin and glutamine also block the inhibition of Ca²⁺ transport caused by GSH depleting drugs.