He reasoned that if an unknown stain caused foaming on treatment with hydrogen peroxide, it probably contained hemoglobin, and was therefore likely to be blood. Introduced in , this was the first presumptive test for blood. But since hydrogen peroxide tends to decompose slowly by itself, looking for extra bubbles was a challenging endeavour. This relied on the chemistry of phenolphthalein, well-known today to students as an acid-base indicator.
Phenolphthalein is colourless in acid but turns a deep pink in a basic solution. In this case, though, the important feature is that phenolphthalein can be reduced with zinc into colourless phenolphthalin, which along with a base is present in the test reagent.
In the usual process, a drop of alcohol is added to an unknown stain to dissolve any hemoglobin that may be present, followed by rubbing with a swab that has been treated with the Kastle-Meyer reagent. A drop of hydrogen peroxide is then applied to the swab. If hemoglobin is present, the hydrogen peroxide decomposes to yield oxygen that in turn oxidizes the phenolphtalin to phenolphthalein.
Since the solution is basic, a pink colour develops indicating the presence of blood. The test is very sensitive, but is not specific for human blood. Animal blood will also yield a positive reaction as will oxidizing agents such as some metal ions. At lower concentration, hydrogen peroxide plays as a signaling molecule while it becomes toxic at higher concentration [ 65 ] and catalase plays an important role in maintaining homeostasis of the cells by degrading hydrogen peroxide.
The activity of catalase in the serum was observed to be high in acute pancreatitis [ 66 ] and persists at its elevated level for as long as 10 to 14 days [ 66 ]. Therefore, the high catalase activity may contribute to the pathogenesis of T3cDM in an indirect way by maintaining the hydrogen peroxide concentration which would induce the synthesis of proinflammatory cytokines resulting in pancreatic diabetes.
Gestational diabetes mellitus GDM is another common form of diabetes among pregnant women. The pathogenesis of GDM is very similar to type 2 diabetes mellitus. There are several factors including ethnicity, maternal age, hypertension, obesity, and polycystic ovary syndrome PCOS which are associated with the possibility of developing GDM [ 67 , 68 ]. Pregnant women with GDM have higher risk of developing type 2 diabetes mellitus after pregnancy [ 68 ].
The offspring of gestational diabetic mothers are prone to development of different diseases like hypertension, different metabolic syndrome, and chronic kidney disease [ 69 , 70 ]. These birth defects might be due to higher concentration of reactive oxygen species and lowering of the antioxidant defense which in turn make the cell more susceptible to oxidative insults [ 70 , 71 ].
GDM usually develops in the second and third trimesters of the pregnancy period. Reports on the link of catalase with GDM are very conflicting. It has been reported that oxidative stress is high in the second and third trimesters of pregnancy and the catalase activity was also low during this period [ 72 , 73 ].
The blood catalase activity has been reported to be low in pregnant women with GDM compared to nonpregnant and pregnant nondiabetic healthy control women [ 72 ]. However, the blood catalase activity was observed to increase in the third trimester than in the second trimester in pregnant individuals with GDM [ 72 ]. In another study, low blood catalase activity has been observed in pregnant women with GDM [ 40 ].
The mRNA expression of the CAT gene in the placenta of gestational diabetic pregnant women was found to be higher in comparison to that in normal pregnant women [ 74 ].
So it may be concluded from the above that catalase might have a relation with GDM pathophysiology during pregnancy, but further research to establish the facts is needed. Hydrogen peroxide has been implicated to act as a cellular messenger in the signaling pathway for insulin secretion by inactivating tyrosine phosphatase [ 65 , 75 — 78 ]. It has been postulated that catalase in the liver may confer cellular protection by degrading the hydrogen peroxide to water and oxygen [ 28 — 31 ].
Lack of catalase can contribute to the development of diabetes mellitus [ 76 , 79 ] with a positive correlation being observed between diabetes mellitus in acatalasemic patients. It is estimated that approximately It was proposed that catalase deficiency may be responsible for the development of diabetes mellitus in an indirect way [ 24 ]. These cells are not only deprived of catalase but also have a higher concentration of mitochondria [ 80 ] which is one of the major sources of superoxide and hydrogen peroxide in the cell through the electron transport pathway.
There are many vascular complications in diabetes mellitus including microvascular complications diabetic retinopathy, nephropathy, neuropathy, etc. Oxidation plays an important role in different complications which occur in both type 1 and type II diabetes. Due to the low expression levels or activity of catalase, the concentration of hydrogen peroxide may increase in the cells creating oxidative stress conditions causing the progression of different types of complications.
In the case of diabetes retinopathy, the retina is damaged by retina neovascularization where new vessel origination from existing veins extends to the retinal inner cells [ 82 ] leading to blindness [ 83 ].
Vascular endothelial growth factor VEGF is a prime inducer of angiogenesis, a procedure of new vessel development. It causes the generation of hydrogen peroxide instead of other reactive species [ 84 ]. Hydrogen peroxide may have a role as a signaling molecule in the VEGF signaling molecule. In a study on a diabetic rat model, high concentration of hydrogen peroxide was observed in the retinal cells, creating oxidative stress conditions within the cell [ 85 ].
Since retinal cells have high content of polyunsaturated fatty acid content [ 86 ], they can be oxidized by the hydroxyl radicals generated from hydrogen peroxide by the Fenton reaction.
High levels of lipid peroxides and oxidative DNA damage have been observed in diabetic retinopathy [ 87 — 90 ]. In a recent study, researchers have been able to distinguish five distinct clusters of diabetes by combining parameters such as insulin resistance, insulin secretion, and blood sugar level measurements with age of onset of illness [ 91 ].
Group 1 essentially corresponds to type 1 diabetes while type 2 diabetes is further subdivided into four subgroups labelled as group 2 to group 5. Individuals with impaired insulin secretion and moderate insulin resistance are labelled under group 2 the severe insulin-deficient diabetes group while in group 3, the severe insulin-resistant diabetes patients with obesity and severe insulin resistance are included. Group 4 is composed of the mild obesity-related diabetes patients who are obese and fall ill at a relatively young age while the largest group of patients is in group 5 with mild age-related diabetes in mostly elderly patients.
A relationship between this new classification of diabetes with catalase expression levels or its activity has still not been probed for a link, if any, and needs further research. Many factors including smoking and diabetes are associated with a higher risk of dementia. Its clinical manifestations include bradykinesia, rigidity, resting tremor, and postural instability. It starts with rhythmic tremor of limbs especially during periods of rest or sleep. At the developing stage of the disease, patients face difficulties in controlling movement and muscle rigidity.
Due to this muscular rigidity, slowness of movement and slowness of initiation of movement occur. The disease is characterized by the exhaustion of dopamine due to damage of dopamine-producing neurons in the substantia nigra pars compacta SNpc [ — ].
The small neurotransmitter molecules like dopamine are synthesized in the cytoplasm and are transferred to small vesicles as it becomes oxidized at the physiological pH.
Vitiligo is one of the chronic pigmentary disorders where skin melanocyte cells—the pigment responsible for the color of the skin—are damaged or are unable to produce melanin. Various studies have shown that the catalase levels in the epidermis of vitiligo patients are lower as compared to those of the healthy control subjects [ , ] with a resultant increase in the concentration of hydrogen peroxide.
In the cell, hydroxyl radicals can be produced spontaneously from hydrogen peroxide through photochemical reduction, i. These hydroxyl radicals are able to oxidize lipids in the cell membrane. This may be the cause behind damage of keratinocytes and melanocytes in the epidermal layer of the skin in such patients [ — ]. Moreover, the inhibitory effect of hydrogen peroxide or allelic modification of the CAT gene results in low catalase activity.
However, it has been observed that there is an erratic relationship between catalase polymorphism and vitiligo. But the results were not observed to be consistent. Though the results are inconsistent from population studies, an interconnection between the pathogenesis and catalase may still be possible as scattered demonstrations are reported in the literature.
Therefore, further studies to understand the link is necessary. Acatalasemia AC is a hereditary disorder which is linked with the anomaly of catalase enzyme affecting its activity. In , Takahara, a Japanese otolaryngologist, first reported this disorder [ , ]. He found that four out of seven races in Japan had the same genetic flaw [ ].
His ex vivo experiments consisted of filling the mouth ulcer of a diseased patient with hydrogen peroxide. Since no bubble formation was observed, he concluded that a catalase or its enzymatic activity is absent in the saliva of the patients.
In honor of his primary findings, this disease was christened as the Takahara disease. Acatalasemia and hypocatalasemia signify homozygotes and heterozygotes, respectively.
The heterozygote of acatalasemia shows half of the catalase activity than normal and this phenotype is known as hypocatalasemia [ ]. Depending on the geographical location from where it has been first studied, there are different types of acatalasemia described as Japanese, Swiss, Hungarian, German, and Peruvian types. Approximately acatalasemic patients have been reported to date from all over the world.
Two kinds of mutations in the catalase gene have been reported to be involved in the Japanese acatalasemia. A splicing mutation has been held responsible for Japanese acatalasemia I where a substitution of a guanine residue with adenine residue at position 5 of intron 4 disturbed the splicing pattern of the RNA product producing a defective protein [ ].
In Japanese acatalasemia II, a frame shift mutation occurs due to the deletion of thymine in position of exon 4 which modifies the amino acid sequence and produces a new TGA stop codon at the 3 terminal. Translation of this mutated strand produces a polypeptide of amino acid residues. This is a truncated protein that is unstable and nonfunctional [ ]. Aebi et al. The study on the fibroblast from Swiss acatalasemia patients suggests that structural mutations in the CAT gene are responsible for inactivation of catalase [ ].
Goth, a Hungarian biochemist, first described Hungarian acatalasemia in after studying the disease in two Hungarian sisters. He found that the catalase activities in the blood of these two acatalasemic sisters were 4.
Studies at his laboratory led Goth to suggest that mutations of the CAT gene and resultant structural changes in the catalase protein are responsible for Hungarian acatalasemia. This laboratory also reported that there was a risk of diabetes mellitus amongst the Hungarian acatalasemic family members though further biochemical and genetic analysis needs to be performed to validate the hypothesis that acatalasemic patients have more chance of developing diabetes mellitus [ 79 ].
There are generally four types of Hungarian acatalasemia which varies according to the different site of gene mutation in the DNA. The same is represented in Table 3. Catalase is one of the most important antioxidant enzymes. As it decomposes hydrogen peroxide to innocuous products such as water and oxygen, catalase is used against numerous oxidative stress-related diseases as a therapeutic agent.
The difficulty in application remains in delivering the catalase enzyme to the appropriate site in adequate amounts. Poly lactic co-glycolic acid nanoparticles have been used for delivering catalase to human neuronal cells, and the protection by these catalase-loaded nanoparticles against oxidative stress was evaluated [ ].
The nanoparticle-loaded catalase showed significant positive effect on neuronal cells preexposed to hydrogen peroxide reducing the hydrogen peroxide-mediated protein oxidation, DNA damage, mitochondrial membrane transition pore opening, and loss of membrane integrity.
Thus, the study suggests that nanoparticle-loaded catalase may be used as a therapeutic agent in oxidative stress-related neurological diseases [ ]. EUK is a salen-manganese complex which has both high catalase and superoxide dismutase activity. It was concluded from these studies on the rat stroke model that EUK may play a protective role in management of this disease.
To study the effect of these fusion proteins under oxidative stress conditions, mammalian cell lines HeLa, PC12 were transduced with purified fusion Tat-CAT and 9Arg-CAT protein and these cells were exposed to hydrogen peroxide. It was found that the viability of the transduced cells increased significantly. It was also observed that when the Tat-CAT and 9Arg-CAT fusion proteins were sprayed over animal skin, it could penetrate the epidermis and dermis layers of the skin.
This study suggests that these fusion proteins can be potentially used as protein therapeutic agents in catalase-related disorders [ ]. Amyotrophic lateral sclerosis ALS is one of the most common types of progressive and fatal neurological disorders which results in loss of motor neurons mostly in the spinal cord and also to some extent in the motor cortex and brain stem.
Rather, the mutated SOD1 has toxic properties with no lowering of the enzymatic activity. This mutated SOD1 protein reacts with some anomalous substrates such as hydrogen peroxide using it as a substrate and produces the most reactive hydroxyl radical which can severely damage important biomolecules [ ]. Mutated SOD1 also has the potential to use peroxynitrite as an atypical substrate leading to the formation of 3-nitrotyrosine which results in the conversion of a functional protein into a nonfunctional one [ ].
Catalase can reduce the hydrogen peroxide concentration by detoxifying it. Therapeutic approaches using putrescine-modified catalase in the treatment of FALS have also been attempted [ ].
It was found that putrescine-catalase—a polyamine-modified catalase—delayed the progression of weakness in the FALS transgenic mouse model [ ]. Thus, the delay in development of clinical weakness in FALS transgenic mice makes the putrescine-modified catalase a good candidate as a therapeutic agent in diseases linked with catalase anomaly. In this connection, it must be mentioned that the putrescine-modified catalase has been reported to exhibit an augmented blood-brain barrier permeability property while maintaining its activity comparable to that of native catalase with intact delivery to the central nervous system after parenteral administration [ ].
Therefore, further studies with this molecule seem to be warranted. Investigations using synthetic SOD-catalase mimetic, increase in the lifespan of SOD2 nullizygous mice along with recovery from spongiform encephalopathy, and alleviation of mitochondrial defects were observed [ ]. Studies using type 1 and type 2 diabetic mice models with fold upregulated catalase expression showed amelioration in the functioning of the cardiomyocytes [ ]. Cardiomyopathy is related to improper functioning of heart muscles where the muscles become enlarged, thick, or stiff.
It can lead to irregular heartbeats or heart failure. Many diabetic patients suffer from cardiomyopathy with structural and functional anomalies of the myocardium without exhibiting concomitant coronary artery disease or hypertension [ ]. As already discussed, catalase is interconnected to diabetes mellitus pathogenesis. It has been observed that a fold increase of catalase activity could drastically reduce the usual features of diabetic cardiomyopathy in the mouse model [ ].
Due to catalase overexpression, the morphological impairment of mitochondria and the myofibrils of heart tissue were prevented. The impaired cardiac contractility was also inhibited with decrease in the production of reactive oxygen species mediated by high glucose concentrations [ ]. So this approach could be an effective therapeutic approach for the treatment of diabetic cardiomyopathy.
An increase in focus on the role of catalase in the pathogenesis of oxidative stress-related diseases and its therapeutic approach is needed. Catalase plays a significant role in hydrogen peroxide metabolism as a key regulator [ 28 , 29 , — ]. Some studies have also shown the involvement of catalase in controlling the concentration of hydrogen peroxide which is also involved in the signaling process [ — ].
Acatalasemia is a rare genetic disorder which is not as destructive as other diseases discussed here, but it could be a mediator in the development of other chronic diseases due to prolonged oxidative stress on the tissues. We have also discussed the risk of type 2 diabetes mellitus among acatalasemic patients. But more research on the biochemical, molecular, and clinical aspects of the disease is necessary. There are many more questions about acatalasemia and its relation to other diseases which need to be answered.
Therefore, further studies are needed to focus on catalase gene mutations and its relationship to acatalasemia and other diseases with decreased catalase activity so that the link can be understood more completely. The therapeutic approaches using catalase needs more experimental validation so that clinical trials can be initiated.
Use of catalase as a medicine or therapy may be a new and broad field of study. Any novel finding about therapeutic uses of catalase will have a huge contribution in medical science. Positive findings can direct towards its possible use for treatment of different oxidative stress-related diseases.
Catalase is one of the crucial antioxidant enzymes which plays an important role by breaking down hydrogen peroxide and maintaining the cellular redox homeostasis. While there are many factors involved in the pathogenesis of these diseases, several studies from different laboratories have demonstrated that catalase has a relationship with the pathogenesis of these diseases.
Research in this area is being carried out by many scientists at different laboratories exploring different aspects of these diseases, but with an ever-increasing aging population, much remains to be achieved.
On the other hand, the potential of catalase as a therapeutic drug in the treatment of several oxidative stress-related diseases is not adequate and is still being explored. Additional research is needed to confirm if catalase may be used as a drug in the treatment of various age-related disorders.
Supplementary Figure 1. In module 1, ACOX1 peroxisomal acyl coenzyme A oxidase , HSD17B4 peroxisomal multifunctional enzyme , and HAO1 hydroxyacid oxidase 1 are involved in the fatty acid oxidation pathway in the peroxisome while the protein DAO D amino acid oxidase is involved in the amino acid metabolism pathway in the peroxisome [ 4 — 6 ] Supplementary Figure 1. Supplementary Materials. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Academic Editor: Cinzia Signorini. Received 25 Mar Revised 18 Jun Accepted 14 Aug Published 11 Nov Abstract Reactive species produced in the cell during normal cellular metabolism can chemically react with cellular biomolecules such as nucleic acids, proteins, and lipids, thereby causing their oxidative modifications leading to alterations in their compositions and potential damage to their cellular activities.
Introduction Reactive species RS are highly active moieties, some of which are direct oxidants, and some have oxygen or oxygen-like electronegative elements produced within the cell during cellular metabolism or under pathological conditions. Table 1. Examples of the various free radicals and other oxidants in the cell [ 2 ]. Figure 1. Relationship between catalase and other antioxidant enzymes. Figure 2. Figure 3. Steps in catalase reaction: a first step; b second step.
Table 2. Physicochemical characteristics of catalase from various sources. Figure 4. Figure 5. Figure 6. Association of catalase polymorphism with risk of some widespread diseases.
Figure 7. Prevalence of diabetes amongst males and females in some countries in data source: World Health Organization-Diabetes Country Profile Types Position of mutation Types of mutation Results of mutation Effect on catalase References Type A Insertion of GA at position in exon 2 occurs which is responsible for the increase of the repeat number from 4 to 5 Frame shift mutation Creates a TGA codon at position Lacks a histidine residue, an essential amino acid necessary for hydrogen peroxide binding [ ] Type B Insertion of G at position 79 of exon 2 Frame shift mutation Generates a stop codon TGA at position 58 A nonfunctional protein is produced [ ] Type C A substitution mutation of G to A at position 5 in intron 7 Splicing mutation No change in peptide chain Level of catalase protein expression is decreased [ , ] Type D Mutation of G to A at position 5 of exon 9 Coding region mutation Replaces the arginine residue to histidine or cysteine Lowering of catalase activity [ ].
Table 3. References K. Halliwell and J. View at: Google Scholar M. Davis, S. Kaufman, and S. The human catalase belongs to this clade and is characterized by a small subunit 62 kDa , with heme b as its prosthetic group and NADPH as cofactor. These proteins have been found in fungi, archeobacteria and bacteria. Their molecular weight varies between and kDa and they are generally homodimers.
The catalase activity degrading hydrogen peroxide is less efficient than in typical catalases but catalase-peroxidases have a better affinity for their substrate H 2 O 2. Catalase-peroxidases are also significantly more sensitive than typical catalases to inactivation by pH and temperature.
The well-known horseradish peroxidase, currently employed in immunoblotting experiments, is one example of catalase-peroxidase. These enzymes have been found exclusively in bacteria.
Manganese catalases utilize two manganese ions in the active site, they can form oligomeric structures measuring between and kDa and have no significant homology with either typical catalases or catalase-peroxidases.
The catalytic reaction is completely different to other types of catalases. Like typical catalases, the catalase reaction occurs in two-step. Human catalase contains four identical subunits of 62 kDa, each subunit containing four distinct domains and one prosthetic heme group Nagem et al. Although amino acid sequences do not have high identities between all typical catalases, the tridimensional structure is highly conserved.
The investigation of inhibitory mechanisms by which cyanide and 3-amino-1,2,4-triazole ATA inhibit human catalase allowed to understand the enzyme activity Putnam et al. Cyanide nitrogen blocks heme access to other potential ligands. It interacts with the distal histidine and an asparagine residue suggesting that it competes with hydrogen peroxide for heme binding. Meanwhile, ATA interacts with the distal histidine leading to an adduct formation and thereby blocks the catalase reaction.
During the enzymatic reaction leading to H 2 O 2 destruction, catalase is first oxidized to a hypervalent iron intermediate, known as compound I Cpd I , which is then reduced back to the resting state by a second H 2 O 2 molecule.
The first reaction is characterized by the oxidation of the heme protein by a single H 2 O 2 molecule leading to the formation of Cpd I , an oxoferryl porphyrin cation radical Jones and Dunford, This second reaction is particularly efficient in some catalases compared to other heme proteins such as myoglobin Matsui et al. Labeling studies have shown that both H 2 O and O 2 molecules are formed from the same molecule of H 2 O 2 Vlasits et al. Fita and Rossmann b proposed that two molecules of H 2 O 2 were sequentially transferred to the oxoferryl group of Cpd I , where the distal histidine residue plays a role of acid-base catalyst.
Although mutation of distal histidine suppresses the ability to form Cpd I Nakatani, , some authors claimed that reaction occurs as a direct mechanism and histidine does not play a crucial role in catalysis Kato et al.
In the presence of one-electron donors such as phenols, ferrocyanide, salicylic acid, NO, superoxide anions and low H 2 O 2 concentrations, Cpd I may undergo a one-electron reduction towards the inactive compound II Cpd II intermediate, which transforms back to the resting state through another one-electron reduction step reviewed in Bauer, In the presence of another one-electron donor, Cpd II will return to a resting state.
In this intermediate state, iron is at an oxyferrous state O 2 -Fe II -heme. Then, Cpd III goes back to a resting state or leads to the inactivation of the catalase.
Regarding catalase localization within the cell, it should be noted that catalase is mainly located in peroxisomes because it contains a sequence signal recognized by some peroxisome receptors. Contrary to mitochondria, proteins located within peroxisomes are all of nuclear origin and should be imported.
Indeed, it is generally accepted that catalase monomers are imported into peroxisomes where tetramerization and heme addition occurs Lazarow and De Duve, The apoprotein monomer enters into the peroxisome by a peroxisome-targeting signal sequence PTS present on the carboxy-terminal tail of catalase.
The most common targeting signal is the SKL serine-lysine-leucine but catalase is characterized by a different signal, namely the KANL lysine-alanine-asparagine-leucine signal Purdue and Lazarow, Some diseases related to defects in peroxisome biogenesis, such as Zellweger syndrome, are characterized by mutations in the PEX5p receptor and cellular H 2 O 2 overproduction due to a catalase default import in peroxisomes Wanders et al.
It has been shown that overexpressing receptor mutants in PEX5-deficient CHO cells, drastically reduce the import of proteins such as catalase Shimozawa et al. Some authors have observed that catalase with the SKL signal and not KANL had a better import capacity and could be transported into the peroxisome even in the case of mutations in the PTS1 receptor Koepke et al.
It has been shown that PEX5p recognizes catalase which is already folded and interacts with other receptors such as PEX13p for proper import into the peroxisome Otera and Fujiki, Studies are underway to validate, through clinical trials, whether catalase SKL has a therapeutic potential for diseases with peroxisome biogenesis disorders.
Recently, it has been reported that PEX19p, an essential protein for peroxisome biogenesis, interacts with Valosin-containing protein VCP and regulates the catalase cytoplasmic localization, a potential feedback mechanism modulating H 2 O 2 levels Murakami et al.
Interestingly, the existence of a cytosolic catalase, in its active tetrameric conformation, has been reported Middelkoop et al. Indeed, catalase may bind cytosolic proteins such as Grb2 and SHP2, to protect them from potential oxidative damage Yano et al. These proteins are linked to the membrane by a pleckstrin homology PH domain, so it is common to find catalase in fractions including membrane proteins and membrane-associated proteins.
In this context, it has been shown that catalase can be localized at the cytoplasmic membrane, specifically at the surface of cancer cells Bauer, Furthermore, localized expression of catalase on the membrane of tumor cells is not in disagreement with the finding of lower total catalase concentration in malignant cells, as the membrane comprises a minority of the total cellular material.
This soluble extracellular catalase was protective for the tumor cells. Finally, catalase has been also localized in the mitochondria of rat cardiomyocytes Radi et al.
The human catalase is expressed in every organ and the highest levels of activity are measured in the liver, kidney and red blood cells Winternitz and Meloy, The first function assigned to catalase is the dismutation of H 2 O 2 into oxygen and water without consummation of endogenous reducing equivalents, an important role in cell defense against oxidative damage by H 2 O 2. To note that H 2 O 2 is not only toxic by its ability to form other ROS, like hydroxyl radical through the Fenton reaction Fenton, but as was nicely recently reviewed by Sies, H 2 O 2 acting as a second messenger is involved in many biological processes including changes of morphology, proliferation, signaling i.
It has also been reported that catalase may decompose peroxynitrite Gebicka and Didik, ; Heinzelmann and Bauer, , oxidize nitric oxide to nitrite Wink and Mitchell, ; Brunelli et al. Catalase also exhibits low oxidase activity O 2 -dependent oxidation of organic substrates Vetrano et al. Thus, catalase may also have additional roles such as the detoxification or activation of toxic and anti-tumor compounds. For instance, catalase has been detected in mouse oocytes most likely to protect the genome from oxidative damage during meiotic maturation Park et al.
Within this framework, several studies have shown a change in catalase expression in cancer cells became resistant to chemotherapies Akman et al. Thus, a potential role of catalase during the acquisition of cancer cell resistance to chemotherapeutic agents was explored by overexpressing the human enzyme in MCF-7 cells, a human derived breast cancer cell line Glorieux et al. No particular resistance against conventional chemotherapies like doxorubicin, cisplatin and paclitaxel was observed in cells overexpressing catalase but they were more resistant to the pro-oxidant effect induced by an H 2 O 2 -generating system Glorieux et al.
In such animals, the development of mitochondrial deletions was reduced and heart disease and the onset of cataracts were delayed. Regarding catalase down-regulation, no particular sensitivity was observed as catalase-deficient mice are viable and fertile Ho et al. They develop normally with a normal hematological profile, but after trauma the mitochondria shows defects in the oxidative phosphorylation.
Note that humans may also be deficient in catalase, a condition known as acatalasemia that is characterized by a low catalase rate, but it is still rare and usually benign Goth et al. In this context, there are benign polymorphisms of the catalase gene for which no change of catalase expression or activity was detected Goth et al. To note that the catalase gene encodes one single protein of amino acids and the single locus has been mapped to chromosome 11p13 Wieacker et al.
The length of the catalase gene is 34 kb, it contains 12 introns and 13 exons generating a mRNA of bp Quan et al. Conversely, some catalase mutations provoke changes in either catalase expression or activity and may be associated with some diseases. Recent studies have focused on the associations of catalase polymorphisms with various types of cancer but many inconsistent results about the relationship between the catalase gene polymorphism and cancer risk were reported.
Recently, two meta-analyses pointed out a correlation exists between this polymorphism CT and prostate cancer Liu et al. Different catalase mutations in patients can cause decreased catalase activity leading to increased H 2 O 2 concentrations in the blood and tissues.
Depending on the mutations, such patients may be subject to an increased risk of type 2 diabetes, vitiligo and increased blood pressure Goth et al. When the mutations are located in exons as in Japanese and Hungarian acatalasemia, a truncated or mutated catalase is synthetized and functionally less active.
This table was adapted from Goth et al. Decreased activity of catalase has also been observed in various genetic alterations, for example, loss of alleles i. It is generally accepted that the cellular maintenance of redox homeostasis is controlled by a complex network of antioxidant enzymes i.
Nevertheless, the molecular mechanisms regulating the expression of catalase — the oldest known and first discovered antioxidant enzyme — are independent of this pathway and not totally elucidated. Therefore, the fine-tuning regulation of this enzyme should be prior elucidated in order to find a new approach to modulate the antioxidant status in cancer cells.
Interestingly, despite the existence of diverse protection mechanisms against oxidant injuries, a consensus emerged in the scientific literature about an alteration of redox homeostasis within tumor cells.
Indeed, they produce large amounts of ROS that are involved in the maintenance of genetic instability favoring cancer cell proliferation. Meanwhile, altered expression levels of catalase have been reported in cancer tissues as compared to their normal counterparts. Thus, as compared to normal tissues of the same origin, some authors reported an increased catalase expression in tumors Sander et al. For instance, we have reported an important decrease of catalase activity in different cancer cell lines, as shown in Table 2 Verrax et al.
Briefly, catalase levels can vary after short treatments to H 2 O 2 Rohrdanz and Kahl, ; Rohrdanz et al. Although mechanisms controlling catalase expression have been partially elucidated, the decreased catalase expression in cancer cells still remains an unanswered question.
Data were analyzed by unpaired t -test. The regulation of catalase expression in cancer cells is a complex process because different levels of regulation are thought to be involved. In a recent review, we discussed the different mechanisms playing a potential role in the regulation of its expression in both healthy and tumor cells Glorieux et al. They include transcriptional regulation, represented by the activity of transcription factors that induce or repress the transcriptional activity of catalase promoters, post-transcriptional regulation mRNA stability and post-translational modification phosphorylation and ubiquitination of the protein.
In addition, epigenetic DNA methylation, modifications of histones changes or genetic alterations can also be involved playing a role in governing proper levels of catalase activity in these cells. Regarding transcription it should be noted that the catalase gene has all the characteristics of a housekeeping gene no TATA box, no INR sequence, high GC content in promoter and a core promoter which is highly conserved among species Quan et al.
In this core promoter, the presence of DNA binding sites for transcription factors like NF-Y and Sp1 has an essential role in the positive regulation of catalase expression Nenoi et al. Additional transcription factors have also been involved in this regulatory process.
Specifically, we investigated the transcriptional regulatory mechanism controlling catalase expression in human mammary cell lines. To this end, we have made a human breast MCF-7 cancer cell line resistant to oxidative stress, the so-called Resox cells.
These cells show decreased ROS basal levels and an increased activity of some antioxidant enzymes, notably catalase Dejeans et al. Thus, cancer adaptation to oxidative stress, regulated by transcriptional factors through chromatin remodeling appears as a new mechanism to target cancer cells. These cells show increased expression of catalase.
HAT: Histobe acetyltransferase. Adapted from Glorieux et al. As previously mentioned, cancer cells are generally deficient in antioxidant enzymes, thus, any increase in ROS levels would be a menace to the precarious redox balance of cancer cells making them vulnerable to an additional oxidative stress. Given that weakness, the loss of redox homeostasis represents an interesting target for research and development of new molecules with antitumor activity and numerous drugs are currently being clinically evaluated.
Therefore, several strategies have been developed looking for the disruption of tumor cell redox homeostasis and a subsequent cancer cell death Demizu et al. One of these strategies is the use of ROS-generating compounds such as arsenic trioxide ATO , currently employed against promyelocytic leukemia Valenzuela et al. Indeed, the impairment of mitochondrial function due to increased levels of superoxide anion is supposed to be the main mechanism of both chemotherapeutic drugs Thayer, ; Pelicano et al.
A decrease in antioxidant levels has also been proposed. The development of specific inhibitors of thioredoxin and thioredoxin reductases was also carried out. Inhibitors of thioredoxin, such as PX, were shown to have potent antitumor activities Welsh et al. Conversely, the overexpression of Trx1 is correlated with resistance to anti-cancer drugs Baker et al. As quinones display redox cycling abilities thus generating ROS Kappus and Sies, , the association of menadione a naphthoquinone derivative and ascorbate Figure 3 , was employed to trigger tumor cell death Verrax et al.
We hypothesized that H 2 O 2 , issued from the redox cycling, is the oxidant species responsible for antitumor effects observed both in vitro and in vivo Verrax et al. The induced oxidative stress provokes cell necrosis by a wide variety of processes including ATP depletion Verrax et al. Based on the vulnerability of tumor cells to an oxidative stress, we have induced the alteration of their intracellular redox homeostasis as a new strategy in the research and development of new antitumor drugs Benites et al.
A similar approach has been recently developed by using the SnFe 2 O 4 nanocrystals, a heterogeneous Fenton catalyst, which once internalized into the cancer cells, convert H 2 O 2 into hydroxyl radicals inducing apoptotic cell death. In normal cells, the oxidative injury induced by SnFe 2 O 4 is prevented by catalase Lee et al. The biological activity showed by menadione mainly relies upon its ability to accept one electron from ascorbate to form a semiquinone radical.
When the semiquinone is reduced back to its quinone form, superoxide anion is produced which by dismutation generates hydrogen peroxide. Despite that Resox cells display high antioxidant defenses Dejeans et al.
Arsenic trioxide ATO decreases catalase expression in breast cancer cells and sensitizes them to pro-oxidant drugs. Under stress conditions, the antioxidant enzyme catalase plays a major role by detoxifying H 2 O 2. As consequences, a change of its activity or expression will lead to pathological processes as Zellweger syndrome, acatalasemia or WAGR syndrome. The subcellular localization of catalase is mainly peroxisomal but a shuttle between this organelle and cytoplasm exists and may be involved in the protection of key cellular elements i.
Our group and others demonstrated that catalase expression is also altered in cancer cells, most likely to favor cell proliferation by inducing genetic instability and activation of oncogenes. The regulation of catalase expression appears to be mainly controlled at transcriptional levels although other mechanisms may also be involved. Therefore, catalase can be a future therapeutic target in the context of cancer by using pro-oxidant approaches. The authors thank Professor Helmut Sies for the splendid discussion and his precious input.
Akca, H. Enzyme Inhib. Search in Google Scholar. Akman, S. Catalase is an enzyme in the liver that breaks down harmful hydrogen peroxide into oxygen and water. When this reaction occurs, oxygen gas bubbles escape and create foam.
Be careful using the sharp knife. An adult may need to help with this. Blend on high speed, pulsing when necessary, until the liver is smooth and no chunks are present. Be careful of the sharp blades in the blender.
To the blended liver drop, add one drop of hydrogen peroxide. You should see a lot of bubbles! What do you think the bubbles are made of? This shows that the liver enzyme catalase is working to start the chemical reaction that breaks down the hydrogen peroxide that would be harmful to the body into less dangerous compounds. What is the color and consistency of this mixture?
Put one drop of the mixture on a clean part of the large plate and add one drop of hydrogen peroxide to it. Compared with the untreated blended liver, did more, less or about the same amount of bubbles form? Did they form more slowly, more quickly or at about the same rate?
Did more, less or about the same amount of bubbles form? Cover the bowl and microwave it on high for 20 seconds. How does the blended liver look after heating? Remove a drop-size amount of the heated liver and put it on a clean part of the large plate.
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