Family Of Isoenzymes Research Articles

A specific amino acid residue in the catalytic site of dandelion polyphenol oxidases acts as 'selector' for substrate specificity.

Successful site-directed mutagenesis combined with in silico modeling and docking studies for the first time offers experimental proof of the role of the 'substrate selector' residue in plant polyphenol oxidases. The plant and fungi enzymes responsible for tissue browning are called polyphenol oxidases (PPOs). In plants, PPOs often occur as families of isoenzymes which are differentially expressed, but little is known about their physiological roles or natural substrates. In a recent study that explored these structure-function relationships, the eleven known dandelion (Taraxacum officinale) PPOs were shown to separate into two different phylogenetic groups differing in catalytic cavity architecture, kinetic parameters, and substrate range. The same study proposed that the PPOs' substrate specificity is controlled by one specific amino acid residue positioned at the entrance to the catalytic site: whereas group 1 dandelion PPOs possess a hydrophobic isoleucine (I) at position HB2+1, group 2 PPOs exhibit a larger, positively charged arginine (R). However, this suggestion was only based on bioinformatic analyses, not experiments. To experimentally investigate this hypothesis, we converted group 1 ToPPO-2 and group 2 ToPPO-6 into PPO-2-I244R and PPO-6-R254I, respectively, and expressed them in E. coli. By performing detailed kinetic characterization and in silico docking studies, we found that replacing this single amino acid significantly changed the PPO's substrate specificity. Our findings therefore proof the role of the 'substrate selector' in plant PPOs.

Off‑target effect of imatinib and nilotinib on human vitamin D3 metabolism.

Prolonged treatment with tyrosine kinase inhibitors (TKI) including imatinib (IMA) or nilotinib (NIL), induces severe disturbances of bone metabolism in patients with chronic myeloid leukaemia. As vitamin D3 (VD3) is involved in the complex cycle of bone remodelling, the present study investigated invitro, the influence of IMA and NIL on VD3 metabolism i)in HaCaT cells and ii)in cultured outer root sheath keratinocytes (ORS‑KC) from hair follicles of IMA treated children. Cells were incubated in the presence of IMA or NIL. Concomitantly, specific inhibitors were applied to analyze the inhibition of the VD3 processing cytochrome P450 isoenzyme family by TKIs. Invitro, IMA and NIL significantly impaired the production of calcitriol in HaCaT and cultured ORS‑KC cells from hair follicles of IMA treated children. For NIL, this inhibitory effect demonstrated a 4‑fold increase. In HaCaT and ORS‑KC, application of specific CYP450 inhibitors revealed that CYP27B1 was impaired by IMA and NIL leading to an intracellular accumulation of calcidiol. However, during TKI treatment, KC of IMA treated children revealed no differences in calcidiol and calcitriol levels. In conclusion, IMA and NIL interfere with the vitamin D3 cascade due to their metabolism by CYP27B1.

Possible role of increased oxidative stress in pulmonary hypertension in experimental diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is one of the causes of respiratory failure in newborns due to lung hypoplasia and pulmonary abnormalities leading to pulmonary hypertension (PH). NAD(P)H oxidase (Nox) is a family of isoenzymes that generate reactive oxygen species (ROS) which can contribute to PH-induced vascular dysfunction. On the other hand, superoxide dismutase (SOD) 1-2 and catalase are the antioxidant enzymes that eliminate the excess of ROS in pulmonary vascular cells. Our aim is to examine whether PH-associated with CDH is due to a dysregulation of ROS production in lungs from CDH fetuses. Pregnant rats received either 100mg nitrofen or vehicle on E9.5. Fetuses were recovered on E21. (1) Nox activity, (2) H2O2 production and (3) mRNA levels of Nox1, Nox2, Nox4, SOD1, SOD2 and catalase were analyzed in fetal lungs. Nox activity and Nox1 and Nox2 mRNA levels were increased in the lungs of fetuses with CDH. However, there were no changes in H2O2 production and Nox4 mRNA levels. SOD1, SOD2 and catalase were decreased. The raised oxidative stress due to increase in ROS generation by Nox isoenzymes and dysfunction of antioxidant enzymes seems to be a potential mechanism responsible on PH-associated with CDH.

Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors.

There is accumulating evidence indicating that aldehyde dehydrogenase (ALDH) activity selects for cancer cells with increased aggressiveness, capacity for sustained proliferation, and plasticity in primary tumors. However, emerging data also suggests an important mechanistic role for the ALDH family of isoenzymes in the metastatic activity of tumor cells. Recent studies indicate that ALDH correlates with either increased or decreased metastatic capacity in a cellular context-dependent manner. Importantly, it appears that different ALDH isoforms support increased metastatic capacity in different tumor types. This review assesses the potential of ALDH as biological marker and mechanistic mediator of metastasis in solid tumors. In many malignancies, most notably in breast cancer, ALDH activity and expression appears to be a promising marker and potential therapeutic target for treating metastasis in the clinical setting.

Purification and stability of octameric mitochondrial creatine kinase isoform from herring (Clupea harengus) organ of vision.

Creatine kinases (CKs) constitute a large family of isoenzymes that are involved in intracellular energy homeostasis. In cells with high and fluctuating energy requirements ATP level is maintained via phosphocreatine hydrolysis catalyzed by creatine kinase. In contrast to invertebrates and higher vertebrates, in poikilothermic vertebrates the adaptations for the regulation of energy metabolism by changes in the oligomeric state of CK isoforms are not well known. The present study aimed at identification of herring eye CK isoforms and focuses on factors affecting the CK-octamer stability. In addition to the CK octamer, three different dimeric isoforms of CK were detected by cellulose acetate native electrophoresis. Destabilization of octamer was studied in the presence of TSAC substrates and about 50% of octamers dissociated into dimers within 24h. Moreover, we found that the increase of temperature from 4 °C to 30 °C caused rapid inactivation of dimers in TSAC-treated samples but did not affect octameric structures. In a thermostability assay we demonstrated that octamers retain their activity even at 50 °C. Our results indicate that destabilization of the octameric structure can lead to loss of enzyme activity at higher temperatures (above 30 °C). Furthermore, our results based on N-terminal sequence analysis suggest that probably the mitochondrial s-type CK, rather than u-type, is predominantly expressed in herring eye. In conclusion the existence of four various CK isoforms in one organ may reflect complex regulation of energy metabolism in the phototransduction process in teleost fishes.

Type I phosphatidylinositol 4-phosphate 5-kinase homo- and heterodimerization determines its membrane localization and activity.

Type I phosphatidylinositol 4-phosphate 5-kinases (PIP5KIs; α, β, and γ) are a family of isoenzymes that produce phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] using phosphatidylinositol 4-phosphate as substrate. Their structural homology with the class II lipid kinases [type II phosphatidylinositol 5-phosphate 4-kinase (PIP4KII)] suggests that PIP5KI dimerizes, although this has not been formally demonstrated. Neither the hypothetical structural dimerization determinants nor the functional consequences of dimerization have been studied. Here, we used Förster resonance energy transfer, coprecipitation, and ELISA to show that PIP5KIβ forms homo- and heterodimers with PIP5KIγ_i2 in vitro and in live human cells. Dimerization appears to be a general phenomenon for PIP5KI isoenzymes because PIP5KIβ/PIP5KIα heterodimers were also detected by mass spectrometry. Dimerization was independent of actin cytoskeleton remodeling and was also observed using purified proteins. Mutagenesis studies of PIP5KIβ located the dimerization motif at the N terminus, in a region homologous to that implicated in PIP4KII dimerization. PIP5KIβ mutants whose dimerization was impaired showed a severe decrease in PI(4,5)P2 production and plasma membrane delocalization, although their association to lipid monolayers was unaltered. Our results identify dimerization as an integral feature of PIP5K proteins and a central determinant of their enzyme activity.

NADPH oxidases, Nox: new isoenzymes family

NADPH oxidases, Nox, are a family of isoenzymes, composed of seven members, whose sole function is to produce reactive oxygen species (ROS). Although Nox catalyze the same enzymatic reaction, they acquired from a common ancestor during evolution, specificities related to their tissue expression, subcellular localization, activation mechanisms and regulation. Their functions could vary depending on the pathophysiological state of the tissues. Indeed, ROS are not only bactericidal weapons in phagocytes but also essential cellular signaling molecules and their overproduction is involved in chronic diseases and diseases of aging. The understanding of the mechanisms involved in the function of Nox and the emergence of Nox inhibitors, require a thorough knowledge of their nature and structure. The objectives of this review are to highlight, in a structure/function approach, the main similar and differentiated properties shared by the human Nox isoenzymes.

Ascorbate peroxidase from Jatropha curcas enhances salt tolerance in transgenic Arabidopsis.

Ascorbate peroxidase (APX) plays a central role in the ascorbate-glutathione cycle and is a key enzyme in cellular H2O2 me-tabolism. It includes a family of isoenzymes with different character-istics, which are identified in many higher plants. In the present study, we isolated the APX gene from Jatropha curcas L, which is similar with other previously characterized APXs as revealed by alignment and phylogenetic analysis of its deduced amino acid sequence. Real-time qPCR analysis showed that the expression level of JcAPX transcript significantly increased under NaCl stress. Subsequently, to elucidate the contribution of JcAPX to the protection against salt-induced oxi-dative stress, the expression construct p35S: JcAPX was created and transformed into Arabidopsis and transcribed. Under 150-mM NaCl stress, compared with wild type (WT), the overexpression of JcAPX in Arabidopsis increased the germination rate, the number of leaves, and the rosette area. In addition, the transgenic plants had longer roots, higher total chlorophyll content, higher total APX activity, and lower H2O2 content than the WT under NaCl stress conditions. These results suggested that higher APX activity in transgenic lines increases the salt tolerance by enhancing scavenging capacity for reactive oxygen spe-cies under NaCl stress conditions.

A glycogene mutation map for discovery of diseases of glycosylation.

Glycosylation of proteins and lipids involves over 200 known glycosyltransferases (GTs), and deleterious defects in many of the genes encoding these enzymes cause disorders collectively classified as congenital disorders of glycosylation (CDGs). Most known CDGs are caused by defects in glycogenes that affect glycosylation globally. Many GTs are members of homologous isoenzyme families and deficiencies in individual isoenzymes may not affect glycosylation globally. In line with this, there appears to be an underrepresentation of disease-causing glycogenes among these larger isoenzyme homologous families. However, genome-wide association studies have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole-exome sequencing (WES) provides access to mutations in, for example, GT genes in populations, which can be used to predict and/or analyze functional deleterious mutations. Here, we constructed a draft of a functional mutational map of glycogenes, GlyMAP, from WES of a rather homogenous population of 2000 Danes. We cataloged all missense mutations and used prediction algorithms, manual inspection and in case of carbohydrate-active enzymes family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP (http://glymap.glycomics.ku.dk) provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs.

Biochemical and pathological studies on peroxidases -an updated review.

Peroxidases represent a family of isoenzymes actively involved in oxidizing reactive oxygen species, innate immunity, hormone biosynthesis and pathogenesis of several diseases. Different types of peroxidases have organ, tissues, cellular and sub-cellular level of specificities in their function. Different diseases lead to varied expressions of peroxidases based on several mechanisms proposed. Several researches are going on to understand its deficiency, over-expression and malfunction in relation with different diseases. Some common diseases of mankind like cancer, cardiovascular diseases and diabetes directly or indirectly involve the role of peroxidases. So the status of peroxidase levels may also function as a marker of different diseases. Although many types of diseases in human beings have a strong correlation with tissue specific peroxidases, the clear role of these oxido-reductases is not yet fully understood. Here we are focusing on the role of peroxidases in relations with different diseases occurring due to oxidative stress.

CYP-dependent Metabolism of Antitumor Pyrazolo[3,4-d]pyrimidine Derivatives Is Characterized by an Oxidative Dechlorination Reaction

The aim of this study is to investigate the metabolic (cytochrome P450-dependent) behaviour of pyrazolo[3,4-d]pyrimidines 1-10 dual Abl/Src kinase inhibitors. All the compounds demonstrate good metabolic stability both in human liver (HLM) and in rat liver (RLM) microsomes. Moreover, all the tested molecules undergo the same metabolic CYP-dependent reactions, namely oxidative dechlorination and N-dealkylation. These metabolic pathways are fully characterized for compound 1. In HLM, the dehalogenated metabolite accounts for about 87% of the full 1 metabolism, while the N-dealkylated metabolite accounts for 12%. Inhibition studies performed using different CYP-inhibitors indicate that the 3A family is the isoenzyme family most involved in pyrazolo[3,4-d]pyrimidine metabolism. This observation is confirmed by studies performed by using CYP3A selective substrates. Furthermore kinetic analysis performed in RLM, HLM and cDNA CYP3A4 shows that the affinity of CYPs towards compound 1 is similar in all the tested preparations (Km = 32.7, 21.8, and 48.7 µM, respectively).

The extended ppGalNAc-T family and their functional involvement in the metastatic cascade.

O-linked glycosylation of proteins begins with the attachment of a single N-acetylgalactosamine (GalNAc) residue to a serine or threonine residue of the polypeptide and glycosylation of proteins can dramatically change their properties, interactions and activities. This initial attachment is catalysed by members of a family of 20 isoenzymes, the UDP-N-α-D-galactosamine: polypeptide N-acetylgalactosaminyltransferases or ppGalNAc-Ts. Why such a large family of isoenzymes are required to perform, apparently, a single function has been the subject of intense interest. The ppGalNAc-Ts, in fact, have overlapping, but distinct, substrate specificities and are differentially expressed in different cells and tissues and under different conditions of differentiation and development, allowing subtle and complex control of cellular glycosylation. Intriguingly, there is a growing body of evidence showing that altered expression of members of this transferase family are a common feature of many types of cancer and, crucially, that the resulting aberrant glycosylation has functional effects. Here, we review what is known of the expression and distribution of these intriguing transferases in health and in malignancy and, for the first time, bring together what is known of the functional and molecular effects of their disregulation in each step of the complex cascade of cancer metastasis.

Regulatory mechanisms after short‐ and long‐term perturbed lysine biosynthesis in the aspartate pathway: the need for isogenes in Arabidopsis thaliana

The aspartate-derived amino acid pathway in plants is an intensively studied metabolic pathway, because of the biosynthesis of the four essential amino acids lysine, threonine, isoleucine and methionine. The pathway is mainly controlled by the key regulatory enzymes aspartate kinase (AK; EC 2.7.2.4), homoserine dehydrogenase (HSDH; EC 1.1.1.3) and 4-hydroxy-tetrahydrodipicolinate synthase (EC 4.3.3.7), formerly referred to as dihydrodipicolinate synthase (DHDPS). They are encoded by isoenzyme families and it is not known why such families are evolutionarily maintained. To gain more insight into the specific roles and regulation of the isoenzymes, we inhibited DHDPS in Arabidopsis thaliana with the chemical compound (N,N-dimethylglycinatoboranyloxycarbonylmethyl)-dimethylamine-borane (DDAB) and compared the short-term effects on the biochemical and biomolecular level to the long-term adaptations in dhdps knockout mutants. We found that DHDPS2 plays a crucial role in controlling lysine biosynthesis, thereby stabilizing flux through the whole aspartate pathway. Moreover, DHDPS2 was also shown to influence the threonine level to a large extent. In addition, the lysine-sensitive AKs, AKLYS1 and AKLYS3 control the short- and long-term responses to perturbed lysine biosynthesis in Arabidopsis thaliana.

Clinically Relevant Drug-Drug and Drug-Food Interactions

Drug interactions arise when the effects of a drug are altered by the co-administration of another drug or food substance. Many factors determine the clinical response seen, including specific drug characteristics, patient age, gender and co-morbidities. The absorption, distribution, metabolism and excretion of a drug all impact upon drug availability at its sites of action and alterations in these processes can result in adverse outcomes. Similarly, the effect of a drug may be altered if co-prescribed with another drug or food substance that acts on the same receptor or physiological system. In recent years, there is a greater understanding of the mechanisms underlying pharmacokinetic and pharmacodynamic drug interactions, including phase I metabolic reactions (involving the family of cytochrome P450 isoenzymes) and the important role played by drug transporter proteins including P-glycoprotein (expressed in many tissues) and organic anion transporters. There is also a growing awareness of the impact that pharmacogenomics has on drug interaction potential, resulting in interindividual variations in drug transport, metabolism and elimination. The number of potential drug interactions is extensive, but the lower incidence seen in clinical practice implies that many of these potential interactions are not clinically relevant. However, with an ageing population, an increasing number of new drugs, more polypharmacy and the growing use of herbal remedies and over-the-counter preparations, the potential for drug interactions is rising and increasing efforts are needed to avoid them. A good knowledge of the mechanisms underlying drug interactions and the promotion of rational and safe prescribing amongst prescribers are essential in predicting (and therefore preventing) drug interactions in clinical practice. A comprehensive evaluation of drug interaction potential is now an integral part of risk assessment during early drug development, and regulatory bodies including the US FDA and the European Medicines Agency have published guidance documents that outline the importance of in vitro and (where appropriate) in vivo studies to predict interactions during drug development. This article discusses the main mechanisms involved in clinically relevant drug-drug and drug-food interactions and outlines some of the studies used to predict them during drug development. Safe prescribing is discussed along with the central role played by regulatory bodies in supporting drug development and postmarketing pharmacovigilance.

Oral Targeting of Protein Kinase C Receptor: Promising Route for Diabetic Retinopathy?

In patients with diabetes, hyperglycemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to the production of vascular endothelial growth factor (VEGF) in the retina. PKC activation and increased concentration of VEGF are likely to play a key role in diabetic microvascular complications, particularly change in vascular permeability, inflammation, fluid leakage and ischemia in the retina. PKC comprises a super family of isoenzymes that is activated in response to various stimuli. The PKC family consists of 12 isomers that possess distinct differences in structure, substrate requirement, expression and localization. PKC isomer selective inhibitors and VEGF trap are likely to be new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease. A new promising therapy for diabetic retinopathy is undergoing Phase III trials, in which they proposed to target PKC βII isomer using Ruboxistaurin by oral administration. Besides retina, PKC βII isomer is found in higher concentration in brain, spleen, etc. So, oral targeting may be a questionable approach since generalized inhibitors may prove toxic in the treatment of diabetic retinopathy and ocular delivery may be a better alternative approach.

A preliminary study on the influence of glutathione S transferase T1 (GSTT1) as a risk factor for late onset Alzheimer's disease in North Indian population

IntroductionOxidative stress plays key role in pathogenesis of Alzheimer's disease. Glutathione S-transferases (GSTs), a family of phase-II isoenzymes, play a critical role in providing protection against electrophiles and products of oxidative stress. Among different classes of GSTs, GSTM1 (Mu) and GSTT1 (theta) are found to be genetically deleted which results in decreased expression of the concerned enzyme. This study aims at preliminary analysis of the frequency of deletion of GSTM1 and GSTT1 and their association with late-onset Alzheimer's disease. Material and methodsIn this study, association of the deletion type polymorphism of GST M1 and T1 as possible risk factors for dementia of Alzheimer's type was studied in 50 patients and 100 controls. Dementia was diagnosed by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, Mini Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scale. Genotyping was done by multiplex Polymerase Chain Reaction (PCR). Associations between null genotype of either GSTM1 and GSTT1 or both with Alzheimer's disease were analyzed by Chi-Square test. ResultsDeletion of GSTT1 was found significantly associated with Alzheimer's disease (χ2=5.08, p=0.02*). ConclusionsThe odds of Alzheimer's disease in null GSTT1 is found to be increased by 2.47 times in comparison to positive GSTT1.

The use of Sildenafil in the Treatment of Persistent Pulmonary Hypertension of the Newborn: A Review of the Literature

Persistent pulmonary hypertension of the newborn (PPHN) is a serious and potentially fatal condition, characterized by hypoxemia due to increased pulmonary vascular resistance (PVR) with resultant shunting of pulmonary blood to the systemic circulation. Inhaled nitric oxide (iNO) has been considered a revolutionary treatment of PPHN. Data show that the use of iNO has reduced the need of ECMO in neonates with severe PPHN, while in moderate PPHN, iNO administration has been associated with a significant decrease in ventilatory support and prevented progression to severe PPHN. Not all neonates respond to iNO therapy though, and phosphodiesterase (PDE) inhibitors with their potent vasodilator properties have evolved as an alternative therapy or as an adjunct to the treatment of PPHN with iNO. There are ten families of PDE isoenzymes. PDE 5 is particularly prevalent in vascular smooth muscle (VSM) and PDE 5 inhibitors, such as sildenafil, have been used in clinical practice. This review provides a comprehensive account of existing data in the literature, from animal and clinical studies, on the use of sildenafil for the treatment of PPHN. Sildenafil may also have a role as a single mode of therapy, since in resource-limited settings the cost of iNO is a serious concern.

Identifying targets and characterizing the role of aPKCs in murine embryonic stem cells

The protein kinase C (PKC) family of isoenzymes plays a pivotal role in maintaining undifferentiated embryonic stem cells (ESC) and in differentiation to specific cell types. We saw that aPKCs are highly expressed in undifferentiated ESC, to elucidate their role in these cells we aimed at identifying direct and indirect aPKC substrates. Using 2‐D phosphoproteomics and a ζ/λ pseudo‐substrate inhibitor peptide we were able to identify 68 proteins whose phosphorylation decreased in the presence of the inhibitor peptide. 34% of the identified proteins were proteins involved in protein folding, stability and synthesis, 27% in metabolism and 13% cytoskeletal elements and associated proteins involved in cell/cell adhesion processes, and cell polarization such as RhoGDI. Most of the identified proteins involved in metabolism were members of the glycolytic pathway. In addition, glucose consumption was reduced in cells treated with the pseudo‐substrate peptide. Metabolomic analysis combined with our proteomics results will help elucidate metabolic processes in which aPKC is involved in undifferentiated ESCs. Together our study indicates that aPKC is involved in cell/cell adhesion and glucose metabolism in undifferentiated ESCs, processes which are known to contribute to ESC self‐renewal.

Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies

Glutathione S-transferases (GSTs) are members of a multigene family of isoenzymes that are important in the control of oxidative stress and in phase II metabolism. Acting non-enzymically, GSTs can modulate signalling pathways of cell proliferation, cell differentiation and apoptosis. Using a molecular epidemiology approach, we have investigated a potential involvement of GSTs in DNA damage processing, specifically the modulation of DNA repair in a group of 388 healthy adult volunteers; 239 with at least 5 years of occupational exposure to asbestos, stone wool or glass fibre, and 149 reference subjects.We measured DNA damage in lymphocytes using the comet assay (alkaline single cell gel electrophoresis): strand breaks (SBs) and alkali-labile sites, oxidised pyrimidines with endonuclease III, and oxidised purines with formamidopyrimidine DNA glycosylase. We also measured GST activity in erythrocytes, and the capacity for base excision repair (BER) in a lymphocyte extract. Polymorphisms in genes encoding three GST isoenzymes were determined, namely deletion of GSTM1 and GSTT1 and single nucleotide polymorphism Ile105Val in GSTP1.Consumption of vegetables and wine correlated negatively with DNA damage and modulated BER. GST activity correlated with oxidised bases and with BER capacity, and differed depending on polymorphisms in GSTP1, GSTT1 and GSTM1. A significantly lower BER rate was associated with the homozygous GSTT1 deletion in all asbestos site subjects and in the corresponding reference group. Multifactorial analysis revealed effects of sex and exposure in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes. These variants affected also SBs levels, mainly by interactions of GSTP1 genotype with exposure, with sex, and with smoking habit; and by an interaction between sex and smoking. Our results show that GST polymorphisms and GST activity can apparently influence DNA stability and repair of oxidised bases, suggesting a potential new role for these proteins in DNA damage processing via DNA damage signalling.

Dual Function of Nitric Oxide in Carcinogenesis, Reappraisal

Nitric oxide, a unique signalling molecule, is synthesized from L-arginine by a family of isoenzymes called nitric oxide synthase. Function of nitric oxide largely depends on the concentrations of surrounding free radicals and redox state. The local concentration of the nitric oxide defines its anti- or protumorigenic function by interacting with DNA or DNA repair enzymes and tumor suppressor gene, p53, as well. Indoleamine 2,3-dioxygenase activity is induced by interferon-gamma in many human cell types or cancer cells. Indoleamine 2,3- dioxygenase depletes locally available L- tryptophan producing cytotoxic metabolite kynurenine. Nitric oxide regulates the indoleamine 2,3-dioxygenase activity in a dose dependent-manner leading to either enhanced immune response or immune tolerance against tumor tissue. Additionally, the overproduction of nitric oxide may also trigger the cyclooxygenase-lipooxygenase pathways. Nitric oxide synthase expression correlates with cyclooxygenase-2 expression in cancer cells. On the other hand, tetrahydrobiopterin acts as the cofactor for nitric oxide synthase and stabilizes nitric oxide synthase dimers. However, tetrahydrobiopterin acts biphasically; under limited concentrations of tetrahydrobiopterin, nitric oxide generates superoxide radicals. Thus the dual action of nitric oxide and its interaction with the related compounds are of concern for their contribution in the development of carcinogenesis. In this review critical links between the nitric oxide and chronic inflammation associated carcinogenesis are summarized.