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January 2006

High glutathione turnover in human cell lines revealed by acivicin inhibition of gamma-glutamyltranspeptidase and the effects of thiol-reactive metals
during acivicin inhibition.

BACKGROUND: Glutathione is the most abundant nonprotein sulfhydryl-containing compound and constitutes the largest component of the endogenous thiol buffer. Glutathione is known to have multifaceted physiological functions and is a critical factor in protecting organisms against toxicity and disease. Intracellular cysteine concentration is a limiting factor for glutathione synthesis. METHODS: In the present study, the metabolism of intra- and extracellular glutathione in HeLa and hepatoma cell cultures is investigated by using different transport inhibitors for cellular uptake of cystine/cysteine. RESULTS: There exist several ways of cystine/cysteine transport into HeLa and hepatoma cells, and inhibition of them decreased intracellular concentration of cystine/cysteine and in some cases also of glutathione. It was also shown that a large pool of total cell culture glutathione was located extracellularly in both HeLa and hepatoma cell cultures when gamma-glutamyltranspeptidase (GT) activity was inhibited by acivicin (ACI). Furthermore, the addition of thiol-reactive metal ions significantly increased the total amount of glutathione in hepatoma cell cultures during acivicin inhibition. Thus, occasional determinations of extracellular concentrations of glutathione without GT inhibition strongly underestimate the total turnover of glutathione in a cell culture. CONCLUSION: This finding has important implications for future research in glutathione metabolism and the understanding of its role in human health and disease.

Clin Chim Acta. 2004 Nov;349(1-2):45-52

The multifood allergy syndrome.

Multiple food intolerance in infants and young children is increasingly diagnosed. More than 40% of infants less than 1 y.o. could be affected. The syndrome is characterized by the seriousness of atopic dermatitis (SCORAD > 50), by enterocolitis or failure to thrive or various associations of symptoms that may change over time. The evolution is long-lasting. Common food allergens are milk, egg, soy, wheat, but other ones can be implicated. The diagnosis is established by standardized oral challenges. Multiple etiopathogenic factors are involved: atopy, gastro-enteritis induced intestinal hyperpermeability, precocity of food diversification, breast-feeding continued after the onset of symptoms. Amino-acid based formulas have changed the evolution.

Allerg Immunol (Paris). 2000 Jan;32(1):12-5

Intestinal permeability in Crohn’s disease patients and their first degree relatives.

BACKGROUND: Family studies suggested that an altered intestinal permeability plays a role in the genesis of Crohn’s disease. AIM: Aim of the present study was to investigate a possible genetic alteration of the mucosal barrier in Crohn’s disease. SUBJECTS: 16 Crohn’s disease patients and 26 of their cohabiting first degree relatives were studied. METHODS: To investigate intestinal permeability, Cellobiose/Mannitol test was administered to both groups. RESULTS: In the two groups, we found that the median intestinal permeability values were higher and statistically different from those obtained in 32 healthy control subjects as well as in five healthy control families. Six (37.5%) Crohn’s disease patients and three (11.5%) of their first degree relatives showed increased individual intestinal permeability values. Intestinal permeability alteration in Crohn’s disease patients was unrelated to sex, age, disease activity, localisation, duration, treatment schedule, as well as to serum anti-Saccharomyces cervisiae antibody positivity in a pilot study conducted in 7 Crohn’s disease patients; anti-Saccharomyces cervisiae antibody values were negative in all 10 first degree relatives investigated. CONCLUSIONS: These findings demonstrate the increase in IP in 37% of the patients and in 11% of their relatives. More extensive investigation of the correlation between ASCA alterations and IP will be needed in both patients with Crohn’s disease and their relatives.

Dig Liver Dis. 2001 Nov;33(8):680-5

Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine.

BACKGROUND: Effect of supplemental alanyl-glutamine in standard TPN (S-TPN) on luminal mucus gel and small intestinal permeability was investigated. METHODS: Thirty Sprague-Dawley rats were divided into group I (n = 10), receiving standard rat diet; group II (n = 10), receiving S-TPN; and group III (n = 10), receiving alanyl-glutamine-supplemented TPN for 1 week. After 1 week, fluorescein isothiocyanate (FITC)-dextran was injected into the small intestine of the rats, and they were killed. A small intestinal sample and portal blood were obtained for morphologic and functional analysis of mucus gel and intestinal permeability. RESULTS: In group II, thickness and optical density of mucus gel per millimeter serosal length of intestine were significantly lower than group I (p<.001) and were significantly higher in group III than in group II (p<.001). The number of goblet cells in the villi and in the crypt of the small intestine was significantly lower in group II than in group I (p<.001) and was significantly higher in group III than in group II (p<.001), with the exception of the villi of jejunum. Villous and crypt surface area per millimeter serosal length of intestine was significantly lower in group II than in group I (p<.001) and was significantly higher in group III than in group II (p<.001). Small intestinal permeability to FITC-dextran was significantly higher in group II than in group I (p<.001) and was significantly lower in group III than in group II (p<.001). Glucosamine synthetase level was significantly higher in group III than in group I and ileum of group II (p<.001). CONCLUSIONS: Alanyl-glutamine-supplemented TPN prevents a decrease in mucus gel and an increase in small intestinal permeability associated with S-TPN.

JPEN J Parenter Enteral Nutr. 1999 Jan-Feb;23(1):24-31

Narrative review: celiac disease: understanding a complex autoimmune disorder.

Celiac disease is a common autoimmune disorder that has genetic, environmental, and immunologic components. It is characterized by an immune response to ingested wheat gluten and related proteins of rye and barley that leads to inflammation, villous atrophy, and crypt hyperplasia in the intestine. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8. Transglutaminase 2 appears to be an important component of the disease, both as a deamidating enzyme that can enhance the immunostimulatory effect of gluten and as a target autoantigen in the immune response. Sensitive and specific serologic tests, including those for anti-transglutaminase antibody, are facilitating fast and noninvasive screening for celiac disease. Thus, they are contributing to a more accurate estimate of the prevalence of the disease and its association with other disorders. Celiac disease is associated with increased rates of anemia, osteoporosis, cancer, neurologic deficits, and additional autoimmune disorders. A gluten-free diet is the mainstay of safe and effective treatment of celiac disease, although its effect on some of the extraintestinal manifestations of the disease remains to be determined.

Ann Intern Med. 2005 Feb 15;142(4):289-98

Whole-body protein metabolism assessed by leucine and glutamine kinetics in adult patients with active celiac disease.

To assess the effect of increased renewal of intestinal epithelial cells on leucine and glutamine (Gln) turnover, 4-hour intravenous infusions of L-[1-(13)C]leucine and L-[2-(15)N]Gln were administered to five adult patients with active celiac disease in the postabsorptive state. There was a 35% increase in leucine flux (micromoles per kilogram per hour) in patients (117 +/- 17) compared with healthy controls (96 +/- 11, P < .03). Gln flux was increased by 13% in patients (377 +/- 35) versus controls (335 +/- 16, P < .04). These results suggest that active celiac disease, characterized by villous atrophy and crypt cell hyperplasia, is associated with a dramatic increase in whole-body protein breakdown as assessed by 13C-leucine, which may contribute per se to the protein malnutrition status of the patients. The increase in Gln utilization as assessed by L-[2-(15)N]Gln was moderate, but may have been offset due to the villose atrophy and ensuing reduced intestinal epithelial cell mass. The results are consistent with the concept that increased renewal of intestinal epithelial cells represents a sizable fraction of whole-body protein turnover and that Gln is an important fuel for epithelial intestinal cells in vivo.

Metabolism. 1998 Dec;47(12):1429-33