Selenium metabolism, selenoproteins and mechanisms of cancer prevention: complexities with thioredoxin reductase

Abstract

Numerous studies in animal models and more recent studies in humans have demonstrated cancer chemopreventive effects with Se. There is extensive evidence that monomethylated forms of Se are critical metabolites for chemopreventive effects of Se. Induction of apoptosis in transformed cells is an important chemopreventive mechanism. Apoptosis can be triggered by micromolar levels of monomethylated forms of Se independent of DNA damage and in cells having a null p53 phenotype. Cell cycle protein kinase cdk2 and protein kinase C are strongly inhibited by various forms of Se. Inhibitory mechanisms involving modification of cysteine residues in proteins by Se have been proposed that involve formation of Se adducts of the selenotrisulfide (S-Se-S) or selenenylsulfide (S-Se) type or catalysis of disulfide formation. Selenium may facilitate reactions of protein cysteine residues by the transient formation of more reactive S-Se intermediates. A novel chemopreventive mechanism is proposed involving Se catalysis of reversible cysteine/disulfide transformations that occur in a number of redox-regulated proteins, including transcription factors. A time-limited activation mechanism for such proteins, with deactivation facilitated by Se, would allow normalization of critical cellular processes in the early stages of transformation. There is uncertainty at the present time regarding the role of selenoproteins in chemoprevention model systems where supranutritional levels of Se are employed. Mammalian thioredoxin reductase is one selenoprotein that shows increased activity with Se supplementation in the nutritional to supranutritional range. Enhanced thioredoxin reduction could have beneficial effects in oxidative stress, but possible adverse effects are considered. Other functions of thioredoxin reductase may be relevant to cell signaling pathways. The functional status of the thioredoxin/thioredoxin reductase system during in vivo chemoprevention with Se has not been established. Some in vitro studies have shown inhibitory effects of Se on the thioredoxin system correlated with growth inhibition by Se. A potential inactivating mechanism for thioredoxin reductase or other selenoenzymes involving formation of a stable diselenide form resistant to reduction is discussed. New aspects of Se biochemistry and possible functions of new selenoproteins in chemoprevention are described.

Selenium status in Southern Tasmania

“…Given that anticarcinogenesis effects have been observed with mono-methylated forms of selenium (Ganther, 1999), only relying on selenoprotein saturation to determine threshold plasma selenium values for cancer prevention in humans may be an inappropriate approach. The implications of the relatively high proportion of subjects with plasma selenium less than 100 mg/l from a population health perspective is unclear at this time.…”

“…One significant limitation with plasma selenium threshold estimates, based on protein levels and activity, is that the positive health effects of selenium cannot be solely attributed to selenoproteins. There is considerable anticarcinogenesis evidence from mono-methylated forms of selenium (Ganther, 1999).…”

Selenium in Biology: Facts and Medical Perspectives

“…In animal experiments, however, individual selenium compounds differed in their efficacy (Ip and Ganther, 1990;Ip, 1998). The protective effect of selenium is not readily explained in terms of prevention of oxidative DNA damage, since, as a rule, higher dosages of selenium than those optimizing peroxide metabolism are required (Combs et al, 1997;Combs and Gray, 1998;Ganther, 1999). Accordingly, topical discussions presume a direct antiproliferative effect of pharmacological selenium concentrations, be it due to enhancement of apoptosis by excess selenium supply or to distinct inhibition of proliferation-enabling enzymatic processes by certain selenium metabolites (Ganther, 1999).…”

Catalytic selenols couple the redox cycles of metallothionein and glutathione

“…Numerous studies have demonstrated cancer-chemopreventive effects of selenium in animals and more recently in humans [24,33,34]. Monomethylated forms of selenium (e.g.…”