Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease

Abstract

Background-Reactive oxygen species contribute to tissue injury in inflammatory bowel disease (IBD). The tripeptide glutathione (GSH) is the most important intracellular antioxidant. Aims-To investigate constituent amino acid plasma levels and the GSH redox status in diVerent compartments in IBD with emphasis on intestinal GSH synthesis in Crohn's disease. Methods-Precursor amino acid levels were analysed in plasma and intestinal mucosa. Reduced (rGSH) and oxidised glutathione (GSSG) were determined enzymatically in peripheral blood mononuclear cells (PBMC), red blood cells (RBC), muscle, and in non-inflamed and inflamed ileum mucosa. Mucosal enzyme activity of -glutamylcysteine synthetase ( GCS) and -glutamyl transferase ( GT) was analysed. Blood of healthy subjects and normal mucosa from a bowel segment resected for tumour growth were used as controls. ). The GSH content was unchanged in PBMC, RBC, and muscle. Conclusions-Decreased activity of key enzymes involved in GSH synthesis accompanied by a decreased availability of cyst(e)ine for GSH synthesis contribute to mucosal GSH deficiency in IBD. As the impaired mucosal antioxidative capacity may further promote oxidative damage, GSH deficiency might be a target for therapeutic intervention in IBD. (Gut 1998;42:485-492) Results-Abnormally

Replenishment of Glutathione Levels Improves Mucosal Function in Experimental Acute Colitis

“…IBD is a multifactorial disease where activation of inflammatory cells are thought to play a key role for its development, however the role of ROS and subsequent oxidative stress as a pathological factor for IBD has not been well defined. Indeed, a large number of previous studies examining the status of antioxidants in mucosa from patients and experimental animal models of colitis have reported a decrease in the levels of antioxidants, including that of GSH (Buffinton and Doe, 1995;Holmes et al, 1998;Lih-Brody et al, 1996;Millar et al, 1996;Sá nchez de Medina et al, 1996;Sido et al, 1998;Zea-Iriarte et al, 1996). However, the temporal relationship and functional consequences of mucosal GSH depletion in the development of colitis have not been clearly established.…”

“…Indeed, the time dependent relationship between mucosal GSH levels and injury score during the acute phase of colitis establish a progressive fall of GSH levels that is accompanied by a worsening of injury induced by TNBSϩethanol. Although it has been known both in humans and rats that mucosal GSH becomes depleted in colitis (Buffinton et al, 1995;Holmes et al, 1998;Lih-Brody et al, 1996;Millar et al, 1996;Sá nchez de Medina et al, 1996;Sido et al, 1998;Zea-Iriarte et al, 1996), its pathophysiological relevance in the course of colitis has not been definitively established. Our work, however, reveal that the depletion of mucosal GSH is an event that occurs early during the induction of colitis, as soon as TNBS reaches cellular GSH.…”

“…Consistent with this effect we report here the induction of ␥-GCS-HS, the catalytic subunit of the rate limiting enzyme in GSH biosynthesis which determines a greater GSH biosynthetic capacity of mucosa 7 days after TNBS treatment. Since the gut is highly dependent on GSH synthesis (Martensson et al, 1990;Sido et al, 1998), the increase in ␥-GCS in mucosa from TNBS-treated rats can be interpreted as an adaptive response to control the consequences of the stress induced by TNBS as ␥-GCS-HS is known to be upregulated in response to divergent stressful conditions including oxidative stress or GSH depletion (Morales et al, , 1998Mulcahy et al, 1997;Rahman et al, 1996;Sekhar et al, 1997;Tian et al, 1997). However, despite almost normalization of mucosal GSH levels in the chronic phases of colitis (1-3 weeks) (Fig.…”

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

“…Decreased GSH in gut epithelial cells may increase susceptibility to oxidative injury and exacerbate degeneration of the intestinal mucosa [28] . Therefore, the elevated activities of glutathione peroxidase (GPX) and catalase (CAT) enzymes observed suggest that TNBS led to the formation of high levels of peroxides, including H 2 O 2 , increasing tissue injury [68] . Nutritional deficiencies have been reported in IBD, such as lower levels of vitamins A, E and C, important natural antioxidants for the organism, as well as a decrease in trace elements such as zinc and selenium, which are crucial components of several antioxidant enzymes such as SOD [69] .…”

Biomarkers for radiation-induced small bowel epithelial damage: An emerging role for plasma Citrulline

“…Intestinal dysfunction resulting from intestinal diseases or injuries affect intermediary and inter-organ metabolism [83][84][85] . Hence, any factor affecting the intestinal mucosal cell mass will have an impact on protein and amino acid metabolism [83,[86][87][88][89][90] .…”