The Putative Role of the Thioredoxin Reductases

In addition to GSH-Px, thioredoxin reductases (TRxRs) (42) deserve particular attention, whose primary function is to catalyze the reduction of the oxidized forms of thioredoxins back into their reduced forms. Thioredoxins are ubiquitous low molecular weight proteins containing two Cys-SH groups in their active reduced forms and a di-sulfide (Cys-S-S-Cys)-linkage in their oxidized forms. Thioredoxins serve as electron donors in a multitude of biologically important reactions, such as DNA synthesis, DNA repair, gene transcription, cell growth, apoptosis, detoxification reactions, including those involving carcinogens, and they in addition help to maintain the functioning of the immune system. The TRxRs have surprisingly low substrate specificity. In addition to the thioredoxins they also reduce protein disulfide isomerase, selenite, selenodiglutathione, nitrosoglutathione, glutathione peroxidase, H2O2, and lipid hydroperoxide reductase, alloxan, and vitamin K, NK lysine disulfide, lipoic acid, dehydroascorbic acid, and the ascorbyl free radical (43). In the physiological hierarchy of the selenoenzymes, the TRxRs fall behind the GSH-Px. Thus, for optimal TRxR activity, higher amounts of selenium are required than for the saturation of GSH-Px activity. The cancer-protective effects of selenium undoubtedly also involves other selenoproteins, of which 25 are encoded in the

Among the effects on the genomic level of tumor cells, selenium has been shown to inactivate the oncogene c-myc and to activate c-fos, causing the partial retransformation of human hepatoma cells

(47). Related to these effects of selenium is the inactivation of MAZ, the c-myc activating zinc finger protein, which regulates the activation of c-myc

(48). These effects of selenium are counteracted by zinc, providing a deeper insight into the mechanism of the zinc-selenium antagonism mentioned above. Selenium has also been shown to inhibit the activation of the nuclear transcription factor NFkB, to activate p53, and to induce apoptosis (49). Selenium may be viewed, in these processes, to act as a catalyst of cellular respiration; the interdependence of its anticarcinogenic effects on oxygen availability has been stressed (50).

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