Glutamine depletion is demonstrated to be an independent predictor of hospital mortality in ICU (intensive care unit) patients. Today glutamine supplementation is recommended to ICU patients on parenteral nutrition. In addition to glutamine, glutathione may be a limiting factor in ICU patients with MOF (multiple organ failure). To study the prevalence of glutamine and glutathione depletion an observational study was performed. The results were analysed in relation to mortality and the conventional predictors of mortality outcome, APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment). Consecutive patients admitted to the ICU at Karolinska University Hospital Huddinge were studied. Patient admission scoring of APACHE II and SOFA were registered as well as mortality up to 6 months. Plasma glutamine concentration and whole blood glutathione status at admittance were analysed. The admission plasma glutamine concentrations were totally independent of the conventional risk scoring at admittance, and a subnormal concentration was an independent predictor of mortality. In addition, glutathione redox status was also an independent mortality predictor, but here a normal ratio was the risk factor. In both cases the mortality risk was mainly confined to the post-ICU period. A low plasma concentration of glutamine at ICU admission is an independent risk factor for post-ICU mortality. The possible benefit of extending glutamine supplementation post-ICU should be evaluated prospectively.

The selenium salt selenite (SeO3 2؊ ) is cytotoxic in low to moderate concentrations, with a remarkable specificity for cancer cells resistant to conventional chemotherapy. Our data show that selenium uptake and accumulation, rather than intracellular events, are crucial to the specific selenite cytotoxicity observed in resistant cancer cells. We show that selenium uptake depends on extracellular reduction, and that the extracellular environment is a key factor specific to selenite cytotoxicity. The extracellular reduction is mediated by cysteine, and the efficacy is determined by the uptake of cystine by the x c ؊ antiporter and secretion of cysteine by multidrug resistance proteins, both of which are frequently overexpressed by resistant cancer cells. This mechanism provides molecular evidence for the existence of an inverse relationship between resistance to conventional chemotherapy and sensitivity to selenite cytotoxicity, and highlights the great therapeutic potential in treating multidrug-resistant cancer.2Ϫ ) efficiently inhibits the growth of malignant cells and studies suggest an inverse relationship between resistance to cytotoxic drugs and sensitivity to selenite (SeO 3 2Ϫ ) (1, 2). A major mechanism of selenite cytotoxicity is thought to be the generation of oxidative stress through intracellular redox cycling of the selenium metabolite selenide with oxygen and cellular thiols, producing nonstoichiometric amounts of superoxide and cellular disulfides. The induction of oxidative stress and consequent apoptosis has been demonstrated in numerous cancer cell lines (2-8), but why this occurs only in malignant cells at easily achievable selenium plasma concentrations remains unclear.With the assumption that the mechanistic explanation is intracellular, studies on differences in cellular uptake have been neglected. Already in the 1960s, selenite (SeO 3 2Ϫ ) was being used experimentally as a tumor-localizing agent. Neoplasms could be detected in brain and thorax in human subjects through i.v. administration of radioactive selenite ( 75 Se) (9). Although at that time the cancer-specific cytotoxic effects of selenite were unknown, and low doses were used (approximately in the nM range in blood) (9), early findings clearly demonstrated that cancer cells enrich selenium in vivo. These findings, combined with current knowledge of selenite's toxic effects on malignant cells, raise the possibility of a cancer-specific high-affinity selenium uptake mechanism that might explain cancer-specific selenite cytotoxicity at therapeutic selenite concentrations (M range).In yeast, millimolar tolerance to selenite can be reduced to the micromolar range by the presence of excessive thiols in the growth medium through high-affinity uptake of a more reduced form of selenite, possibly selenide (10). High-affinity uptake of selenium through the addition of extracellular thiols also has been demonstrated in a keratinocyte model (11) using nanomolar concentrations of selenite. Selenium uptake was prevented in keratinocytes by the ...

The Grx (glutaredoxin) proteins are oxidoreductases with a central function in maintaining the redox balance within the cell. In the present study, we have explored the reactions between selenium compounds and the glutaredoxin system. Selenite, GS-Se-SG (selenodiglutathione) and selenocystine were all shown to be substrates of human Grx1, implying a novel role for the glutaredoxins in selenium metabolism. During the past few years, selenium has further evolved as a potential therapeutic agent in cancer treatment, and a leading mechanism of cytotoxicity is the generation of ROS (reactive oxygen species). Both selenite and GS-Se-SG were reduced by Grx1 and Grx2 in a non-stoichiometric manner due to redox cycling with oxygen, which in turn generated ROS. The role of Grx in selenium toxicity was therefore explored. Cells were treated with the selenium compounds in combination with transient overexpression of, or small interfering RNA against, Grx1. The results demonstrated an increased viability of the cells during silencing of Grx1, indicating that Grx1 is contributing to selenium toxicity. This is in contrast with TrxR (thioredoxin reductase), which previously was shown to protect cells from selenium cytotoxicity, verifying a diverse role between Grx and TrxR in selenium-mediated cytotoxicity. Furthermore, selenium treatment led to a marked increase in protein glutathionylation and cysteinylation that potentially can influence the activity and function of several proteins within the cell.

This study demonstrates that glutathione remains depleted in whole blood. This contrasts to what has previously been shown in skeletal muscle where a restitution of glutathione concentration is seen.