The cell and tissue distribution of thioredoxins and thioredoxin reductases has been the focus of intense research and has also been reviewed in some depth [2, 7]. In contrast, only a handful of studies have so far been aimed at describing the expression pattern and function of Prdx enzymes and Srx in different cell types or organs of the body. Peroxiredoxins appear to be widely expressed in different organs of the body , and the intracellular distribution of the different isoforms also appears to be fairly promiscuous. Nonetheless, the different isoforms are likely to play distinct roles, and tissue/organ-specific differences can be seen in their expression patterns.
Differential expression of Prdx 1 and Prdx 2 in normal human brain cell types has been detected . Prdx 1 is mainly present in astrocytes, in the white matter, ependymal and subependymal cells and in the basal ganglia, substantia nigra and spinal cord, while Prdx 2 is mostly present in large neurons and axons. Both Prdx 1 and Prdx 6 are expressed in glial cells (oligodendrocytes, astrocytes and microglia), but not in neurons [183, 184]. The other Prdx isoforms (2, 3, 4, 5) are expressed in neurons . Prdx 2 is abundant in vitro in type 2 astrocytes, where it might play a role in the ATP-induced stress response. Indeed, ATP in type-2 astrocytes was demonstrated to stimulate the expression of HSP60, Cu,Zn-SOD and a pi shift of Prdx 2 from the oxidized to the reduced form .
Although all six Prdx isoforms are present in the lung, Prdx 6 is predominant. High concentrations of Prdx 6 can be found in Clara cells in airways, and in type II epithelial cells and macrophages in alveoli . In a study by Knoops et al. , highest mRNA levels of Prdx 6 were detected in human thyroid gland, trachea, kidney, lung, adrenal gland, heart and colon. Prdx 3 and Prdx 6 appear highly expressed in healthy ovarian tissue as opposed to ovarian cancer, where several isoforms are dysregulated . Prdx 4 is highly expressed in testis, ovary, heart, liver, skeletal muscle and pancreas, and a relatively high expression has also been described in spleen, thymus, prostrate, small intestine, colon, lung and placenta, whereas leukocytes and brain show low expression levels . Prdx 2, besides being abundant in erythrocytes, is also highly expressed in the adrenal gland, brain and lung of rats, and relatively high expression was detected in rat spleen, gastric smooth muscle, skeletal muscle, liver and kidney extracts .
With a concentration of approximately 5-10 ng per mg total cellular protein, human Srx is most abundant in kidney, lung, spleen and thymus, and relatively abundant in placenta, the central nervous system and the colon . The distribution of sestrin 1 in human tissues seems to be ubiquituous .
The importance of the Prdx-based system enzymes in erythrocytes is well established. Because of their role in oxygen transport, erythrocytes are particularly exposed to oxidative stress. While antioxidant enzymes such as Cu,Zn-SOD (SOD1), catalase and the Grx system are all present in erythrocytes, Prdx 2 is a very abundant antioxidant enzyme in erythrocytes; Prdx 1 and Prdx 6 also occur in erythrocytes [22, 188]. Being so abundant in erythrocytes, peroxiredoxins 1 and 2 presumably contribute with well-defined, specific functions to the redox balance of these cells, and probably fill other functional niches as well. Confirming this assumption, Rabilloud et al.  demonstrated that Prdx 2 accumulates in erythrocytes by the proerythroblast stage, preceding hemoglobin accumulation. Intensive hemoglobin synthesis during the erythroblast stage could lead to extensive hydroxyl radical (HO") formation via the Fenton reaction. The authors suggested that Prdx 2 could have a role in scavenging HO" radicals, as these cannot be destroyed by other antioxidants present in the erythrocytes . Apparently, human erythrocyte Prdx 2 is highly resistant to overoxidation when compared with Jurkat cell Prdx 2, which also counts toward a role for erythrocyte Prdx 2 as a "robust" antioxidant .
Box 6.3: Oxidative Stress, ROS and the Various Implications for Cancer Initiation, Promotion and Progression
The relationship between oxidative stress and cancer is highly complicated. We will therefore need to map out a couple of key points. First, oxidative stress may be involved in the aetiology of cancer. This is true, for instance, in the case of oxidative stress caused by radiation. Oxidative stress is associated with various reactive oxygen species (ROS), such as HO" radicals, which readily modify DNA bases which may then lead to DNA mutations. Ultimately, these mutations may - but do not necessarily have to - result in cancer cell formation. Second, many types of cancer exhibit an abnormal redox profile, for instance caused by an increased metabolic rate or a changed enzymatic profile. A range ofcancer types have been associated with oxidative stress, while others, such as tumors growing under hypoxic conditions, possess a reducing intracellular redox environment. Third, ROS may stimulate cancer cell proliferation, such as the growth of tumors. This effect is due to cell signaling events controlled by redox processes. Hydrogen peroxide, for instance, is able to stimulate cancer cell growth at lower doses. In contrast, higher doses of ROS may kill cancer cells by inducing apoptosis. Such processes are complicated, to say the least, and molecules such as H2O2 may prevent apoptosis (for instance by inhibiting caspase-3 activity), as well as inducing apoptosis in some circumstances. Not surprisingly, the control of oxidative stress and ROS plays a major role in research into the prevention and therapy of many cancers (see Chapters 16 to 19).
At the same time, although Trx 1 and TR 1 are present in erythrocytes , TR activity seems to be very low in these cells, and the reduction of sulfenic acid Prdx 2 to the active thiol form is a very slow process. Low et al. , using a thiol-blocking agent before erythrocyte lysis, followed by immunoblotting, concluded that Prdx 2 was mostly present as a reduced monomer form in erythrocytes, and dimerization occurred as a result of oxidation. Prdx 2 also participates in the regulation of the Gardos channels in erythrocytes, as mentioned above. The erythrocyte membrane is altered in both Duchenne muscular dystrophy and myotonic muscular dystrophy , and thus it is a possibility that Prdx 2 has a role in these conditions.
Changing expression levels of Prdx S are also involved in erythrocyte differentiation: Prdx S is stably expressed in CDS4+ hematopoietic stem cells. Prdx S content diminishes in the proerythrocyte stage and its expression is increased again in terminally differentiated erythrocytes . Intriguing new reports show that the forkhead transcription factor FOXOS plays a critical role in the oxidative stress resistance of progenitor cells during erythropoiesis [172, 19S]. Considering that FOXOS is required for Prdx S expression at least in human cardiac fibroblasts , and FOXOS deficiency results in increased expression of sestrin 2 in mice , it is likely that the vital effects of FOXO3 during erythropoiesis are at least partly mediated through the enzymes of the Prdx-based system.
Prdx 1 and Prdx 2 knockout mice - although outwardly healthy-looking and fertile -suffer from severe hemolytic anemia [27, 43]. Eythrocytes of Prdx mice contain an increased amount of ROS, leading to hemoglobin oxidation and hemolysis . Loss of Prdx 2 results in very similar symptoms, including increased oxidative stress leading to methemoglobin formation and protein oxidation, which again causes Heinz body formation (Heinz bodies are precipitants of denatured globin caused by oxidation of thiol groups), abnormal erythrocyte shape and ultimately hemolysis. Perhaps not surprisingly, Prdx animals are characterized by decreased hemat-ocrit levels and splenomegaly.
Increased reticulocyte counts and erythropoietin levels of Prdx mice indicate compensatory mechanisms of the body . The fact that Prdx 1 or Prdx 2 knockout animals are viable seems surprising at first. Peroxiredoxins may have partially overlapping functions in cells, however, and the knockout of one perox-iredoxin can possibly be compensated for partially by the increased expression of other isoforms. Within this context, it is worth pointing out that Cu,Zn-SOD (SOD1) knockout mice - similarly to Prdx 1 and Prdx 2 knockout mutants - appear to develop normally. Nonetheless, absence of SOD1 causes increased oxidative stress in erythrocytes, leading to oxidation of erythrocyte components, and hemolysis. This in turn leads to autoantibody formation, as extracellular, oxidized erythrocyte components are recognized as antigens . The disease-specific distribution of the Prdx-based system enzymes will be discussed in more depth as part of Chapter 18.
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