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Archives of Toxicology (v.87, #2)

Hepatocellular cancer by P. Godoy; H. M. Bolt (pp. 225-226).

Cellular and molecular mechanisms of hepatocellular carcinoma: an update by Rajagopal N. Aravalli; Erik N. K. Cressman; Clifford J. Steer (pp. 227-247).

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor that accounts for ~80 % of all liver cancer cases worldwide. It is a multifactorial disease caused by a variety of risk factors and often develops in the background of underlying cirrhosis. A number of cellular phenomena, such as tumor microenvironment, inflammation, oxidative stress, and hypoxia act in concert with various molecular events to facilitate tumor initiation, progression, and metastasis. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. Intense research in this multitude of areas has led to significant progress in our understanding of cellular processes and molecular mechanisms that occur during multistage events that lead to hepatocarcinogenesis. In this review, we discuss the current knowledge of HCC, focusing mainly on advances that have occurred during the past 5 years and on the development of novel therapeutics for liver cancer.

Keywords: Hepatocellular carcinoma; Cancer stem cell; Liver cancer; Targeted therapy; microRNA

Impact of lead and mercuric ions on the interleukin-2-dependent proliferation and survival of T cells by Andrea Jorissen; Laura M. Plum; Lothar Rink; Hajo Haase (pp. 249-258).

Mercury and lead are widespread in the environment, causing chronic exposure of a large population to low concentrations of these metals. While several studies demonstrated that low levels of both metals affect the immune system, little is known about underlying molecular mechanisms. The objective of this study was to investigate the impact of mercuric (Hg²⁺) and lead (Pb²⁺) ions on T cells. Up to 100 μM Pb(NO₃)₂ had no effect on cellular viability and proliferation. In contrast, HgCl₂ caused a concentration-dependent decline of viable leukocytes and especially of activated T cells. Additionally, Hg²⁺ induced reactive oxygen species (ROS) generation accompanied by the loss of mitochondrial transmembrane potential, measured by Dihydrorhodamine and Rhodamine-123, respectively. The antioxidant N-acetylcysteine partially reversed the toxic effects of Hg²⁺, pointing to an involvement of ROS. The major cytokine controlling T-cell survival and proliferation is interleukin (IL)-2. Hg²⁺ had no effect on the secretion of IL-2, but on IL-2 mediated signal transduction pathways, reducing phosphorylation of the downstream kinases ERK1/2 and AKT. Moreover, Hg²⁺ led to an arrest of the cells in the S phase of the cell cycle. Taken together, these data fit a model in which Hg²⁺ disrupts mitochondria, and the resulting release of ROS inhibits IL-2-dependent signal transduction, reducing proliferation and survival of T cells.

Keywords: Mercury; Lead; T cells; IL-2; Proliferation; ROS

Hard-metal (WC–Co) particles trigger a signaling cascade involving p38 MAPK, HIF-1α, HMOX1, and p53 activation in human PBMC by Noömi Lombaert; Eleonora Castrucci; Ilse Decordier; Paul Van Hummelen; Micheline Kirsch-Volders; Enrico Cundari; Dominique Lison (pp. 259-268).

Hard-metals are made of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties. While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC–Co particle mixture was shown to increase the risk of lung cancer in exposed workers. We have previously shown that WC–Co specifically induces a burst of reactive oxygen species (ROS) and in vitro mutagenic/apoptogenic effects in human peripheral blood mononucleated cells (PBMC) used as a validated experimental model. In the present study, PBMCs were treated during a short period (15 min) to focus on the very rapid ROS burst induced by WC–Co. We investigated by microarray the response to WC–Co versus Co²⁺ ions (CoCl₂) after 15 min exposure and found that the oxidative stress response HMOX1 gene was highly expressed in WC–Co-treated samples. This result was confirmed by qRT-PCR, and western blotting was carried out to analyze translational and post-translational regulation of genes belonging to the HMOX1 pathway. We show here that WC–Co, and metallic Co particles although with slower kinetics, but not CoCl₂ or WC alone, induced a temporally ordered cascade of events. This cascade implies p38/MAP kinase activation, HIF-1α stabilization, HMOX1 transcriptional activation, and ATM-independent p53 stabilization. These events, and in particular HIF-1α stabilization, could contribute to the carcinogenic activity of WC–Co dusts.

Keywords: Hard-metals; Gene expression; MAPK; HIF-1α; HMOX1

Multidrug resistance-associated proteins are involved in the transport of the glutathione conjugates of the ultimate carcinogen of benzo[a]pyrene in human Caco-2 cells by Stefanie Hessel; Andrea John; Albrecht Seidel; Alfonso Lampen (pp. 269-280).

A wide variety of contaminants are ingested through food, among them the pro-carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) that is resorbed and partially metabolized in the enterocytes of the small intestine. Previous in vitro studies have revealed that BP phenols are excreted as Phase II metabolites including glucuronides and sulfates. This export is mediated by the breast cancer resistance protein (ABCG2). The ultimate carcinogenic Phase I BP metabolite anti-BP-7,8-dihydrodiol-9,10-epoxide (BPDE) can be detoxified by glutathione conjugate formation catalyzed by glutathione S-transferases. In the present study, differentiated human intestinal Caco-2 cells were used as a model for the human small intestine to investigate the detoxification of BPDE and excretion of stereoisomeric glutathione conjugates in the presence of an inhibitor of the glutathione-cleaving enzyme γ-glutamyl transpeptidase at the cell surface. The results indicate that the glutathione conjugates of BPDE are formed and excreted mainly to the apical and to a minor extent to the basolateral side of polarized Caco-2 monolayers. Inhibition studies revealed that the multidrug resistance-associated proteins (ABCCs) are involved in the transport of BPDE glutathione conjugates. Stable ABCC1, ABCC2 and ABCC3 knockdown cell lines were generated, thus making it possible to demonstrate that ABCC1 mediates the basolateral and ABCC2 the apical excretion of BPDE glutathione conjugates. In conclusion, the ultimate carcinogen BPDE is detoxified via glutathione conjugation and subsequently excreted by Caco-2 cells in both apical and basolateral directions. This finding is equivalent to a transport into feces as well as blood system in the in vivo situation.

Keywords: Polycyclic aromatic hydrocarbons; Benzo[a]pyrene; Multidrug resistance-associated proteins; Caco-2 cells

Quantitative structure–activity relationships for organophosphates binding to acetylcholinesterase by Christopher D. Ruark; C. Eric Hack; Peter J. Robinson; Paul E. Anderson; Jeffery M. Gearhart (pp. 281-289).

Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure–activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William’s plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <−2, indicating potential outliers or activity cliffs. The results show that the HOMO–LUMO energy gap contributed most significantly to the binding affinity. A mean training R ² of 0.80, a mean test set R ² of 0.76 and a consensus external test set R ² of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in physiologically based pharmacokinetic/pharmacodynamic models of organophosphate toxicity to determine the rate of acetylcholinesterase inhibition.

Keywords: QSAR; Organophosphate; PBPK/PD; Chemical warfare nerve agent; Acetylcholinesterase; Bimolecular

The role of residues T248, Y249 and T422 in the function of human pregnane X receptor by Aneta Doricakova; Aneta Novotna; Radim Vrzal; Petr Pavek; Zdenek Dvorak (pp. 291-301).

The pregnane X receptor (PXR) is a key xenobiotic receptor that regulates the expression of numerous drug-metabolizing enzymes. Some posttranslational mechanisms modulate its transcriptional activity. Although several kinases have been shown to directly phosphorylate this receptor, little is known about phosphorylation sites of PXR. In the present work, we examined T248, Y249 and T422 putative phosphorylation sites determined based on in silico consensus kinase site prediction analysis. T248 and T422 residues are critical for the interaction of the PXR ligand-binding domain and the activation function-2 (AF2) domain. Site-directed mutagenesis analysis was performed to generate phospho-deficient and phospho-mimetic mutants. We examined transactivation activity of the PXR mutants in gene reporter assays, formation of PXRmutant/RXRα heterodimer, binding of PXR mutants to the CYP3A4 gene response element DR3 and CYP3A4 expression in HepG2 cells after expression of the mutants. We found that T248D mutant activated CYP3A4 transactivation constitutively regardless of the presence or absence of a ligand. Contrary, T248V mutant exhibited low basal and ligand-inducible transactivation capacity as compared to wild-type PXR. Dose–response analysis revealed reduced ligand-dependent transactivation potency of PXR Y249D mutant. Transactivation of the CYP3A4 promoter was abolished with T422A/D mutants. All PXR mutants formed heterodimer with RXRα at a similar level to that observed with wild-type PXR. The ability to bind to DNA in vitro was substantially decreased in case of T248D, T422D and T248V mutants. Our data thus indicate that phosphorylation of T248, Y249 and T422 residues may be critical for the both basal and ligand-activated function of PXR.

Keywords: Drug metabolism; Pregnane X receptor; Cytochrome P450; Phosphorylation

Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells by Diana Ivanova; Hinrich Gronemeyer; Pablo Steinberg; Heinz Nau (pp. 303-310).

The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy.

Keywords: Anti-cancer agents; Apoptosis; Caspases; Enantioselectivity; Leukemia cells

Metallothionein blocks oxidative DNA damage in vitro by Wei Qu; Jingbo Pi; Michael P. Waalkes (pp. 311-321).

The role of metallothionein (MT) in mitigation of oxidative DNA damage (ODD) induced by either cadmium (Cd) or the direct oxidant hydrogen peroxide (H₂O₂) was systematically examined using MT-I/II double knockout (MT-null) or MT-competent wild-type (WT) cells. Both toxicants were much more lethal to MT-null cells (Cd LC₅₀ = 6.6 μM; H₂O₂ LC₅₀ = 550 μM) than to WT cells (Cd LC₅₀ = 16.5 μM; H₂O₂ LC₅₀ = 930 μM). Cd induced concentration-related MT increases in WT cells, while the basal levels were undetectable and not increased by Cd in MT-null cells. ODD, measured by the immuno-spin trapping method, was minimally induced by sub-toxic Cd levels (1 or 5 μM; 24 h) in WT cells, but markedly increased in MT-null cells (>430 %). Similarly, ODD was induced to higher levels by lower concentrations of H₂O₂ in MT-null cells than WT cells. Transfection of MT-I into MT-null cells reduced both Cd- and H₂O₂-induced cytolethality and ODD. Cd increased the expression of the oxidant defense genes, HO-1, and GSTa2 to a much greater extent in MT-null cells than in WT. Cd or H₂O₂ exposure increased the expression of key transport genes, Mrp1 and Mrp2, in WT cells but not in MT-null cells. MT protects against Cd- and H₂O₂-induced ODD in MT-competent cells possibly by multiple mechanisms, potentially including direct metal ion sequestration and sequestration of oxidant radicals by MT. MT-deficient cells appear to adapt to Cd primarily by turning on oxidant response systems, while MT-competent cells activate MT and transport systems.

Keywords: DNA; Cadmium; Oxidative damage; Metallothionein; Cancer

Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study by Elisa C. M. Tonk; Didima M. G. de Groot; André P. M. Wolterbeek; André H. Penninks; Ine D. H. Waalkens-Berendsen; Aldert H. Piersma; Henk van Loveren (pp. 323-335).

The susceptibility of developing immune system to chemical disruption warrants the assessment of immune parameters in reproductive and developmental testing protocols. In this study, a wide range of immune endpoints was included in an extended one-generation reproduction toxicity study (EOGRTS) design to determine the relative sensitivity of immune and developmental parameters to ethanol (EtOH), a well-known developmental toxicant with immunomodulatory properties. Adult Wistar rats were exposed to EtOH via drinking water (0, 1.5, 4, 6.5, 9, 11.5 and 14 % (w/v EtOH)) during premating, mating, gestation and lactation and continuation of exposure of the F₁ from weaning until killed. Immune assessments were performed at postnatal days (PNDs) 21, 42 and 70. Keyhole limpet hemocyanin (KLH)-specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate as well as adaptive immune responses. The most sensitive immune parameters included white blood cell subpopulations, ConA-stimulated splenocyte proliferation, LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific immune responses. Most parameters showed recovery after cessation of EtOH exposure after weaning in the 14 % exposure group. However, effects on LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific parameters persisted until PND 70. The results demonstrate the relative sensitivity to EtOH of especially functional immune parameters and confirm the added value of immune parameters in the EOGRTS. Furthermore, this study identified an expanded KLH-specific parameter set and LPS-induced NO and TNF-α production by adherent splenocytes as valuable parameters that can provide additional information on functional immune effects.

Keywords: Extended one-generation reproductive toxicity study; Developmental immunotoxicity; Benchmark dose approach; Ethanol

Pharmacokinetics explain in vivo/in vitro discrepancies of carcinogen-induced gene expression alterations in rat liver and cultivated hepatocytes by Markus Schug; Regina Stöber; Tanja Heise; Hans Mielke; Ursula Gundert-Remy; Patricio Godoy; Raymond Reif; Meinolf Blaszkewicz; Heidrun Ellinger-Ziegelbauer; Hans-Jürgen Ahr; Silvia Selinski; Georgia Günther; Rosemarie Marchan; Meinolf Blaszkewicz; Agapios Sachinidis; Andreas Nüssler; Axel Oberemm; Jan G. Hengstler (pp. 337-345).

Cultivated hepatocytes represent a well-established in vitro system. However, the applicability of hepatocytes in toxicogenomics is still controversially discussed. Recently, an in vivo/in vitro discrepancy has been described, whereby the non-genotoxic rat liver carcinogen methapyrilene alters the expression of the metabolizing genes SULT1A1 and ABAT, as well as the DNA damage response gene GADD34 in vitro, but not in vivo. If the collagen sandwich cultures of hepatocytes really produce false-positive data, this would compromise its application in toxicogenomics. To revisit the putative in vivo/in vitro discrepancy, we first analyzed and modeled methapyrilene concentrations in the portal vein of rats. The relatively short half-life of 2.8 h implies a rapid decrease in orally administered methapyrilene in vivo below concentrations that can cause gene expression alterations. This corresponded to the time-dependent alteration levels of GADD34, ABAT and SULT1A1 RNA in the liver: RNA levels are altered 1, 6 and 12 h after methapyrilene administration, but return to control levels after 24 and 72 h. In contrast, methapyrilene concentrations in the culture medium supernatant of primary rat hepatocyte cultures decreased slowly. This explains why GADD34, ABAT and SULT1A1 were still deregulated after 24 h exposure in vitro, but not in vivo. It should also be considered that the earliest analyzed time point in the previous in vivo studies was 24 h after methapyrilene administration. In conclusion, previously observed in vitro/in vivo discrepancy can be explained by different pharmacokinetics present in vitro and in vivo. When the in vivo half-life is short, levels of some initially altered genes may have returned to control levels already 24 h after administration.

Keywords: Hepatocyte in vitro system; Alternative methods; In vitro/in vivo comparison; Genotoxic and non-genotoxic carcinogens; In vitro pharmacokinetics

Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity by Shahaf Katalan; Shlomi Lazar; Rachel Brandeis; Ishai Rabinovitz; Inbal Egoz; Ettie Grauer; Eugenia Bloch-Shilderman; Lily Raveh (pp. 347-360).

Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic–clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks.

Keywords: Sarin; Magnesium sulfate; Midazolam; Caramiphen; TSPO; ECoG

Effects of mycophenolic acid alone and in combination with its metabolite mycophenolic acid glucuronide on rat embryos in vitro by Flavia Schmidt; Kathrin Eckardt; Mehdi Shakibaei; Petra Glander; Ralf Stahlmann (pp. 361-370).

Mycophenolic acid (MPA) is an immunosuppressive agent that acts as a selective, non-reversible inhibitor of the enzyme inosine-5′-monophosphate dehydrogenase (IMPDH). Malformations have been described in children after maternal exposure to mycophenolate. However, the causal link is unclear in most cases because women had been treated with a combination of drugs and birth defects may have other causes. Therefore, it is important to study the action of this drug and its main metabolite on embryonic tissue. We studied the teratogenic potential of MPA and its major metabolite, the mycophenolic acid glucuronide (MPAG) in the rat whole-embryo culture. A total of 147 day 9.5 embryos were cultivated for 48 h in the standard medium containing 85 % serum. We tested MPA at concentrations of 0.1; 0.25; 0.5; 0.75 mg/l (0.31; 0.78; 1.56; 2.34 μM) and MPA glucuronide at concentrations of 3; 10; 30; 100 mg/l (6.04; 20.14; 60.43; 201.43 μM). Both substances are highly protein bound, and MPA glucuronide might displace MPA from protein binding. Therefore, we examined whether the effects of MPA can be enhanced when studied in combination with the glucuronide. Furthermore, the focus was on additional endpoints to the standard evaluation of cultivated embryos, such as development of cranial nerves [trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X)] after staining with an antibody against 2H3 neurofilament. Ultrastructural changes were evaluated by electron microscopy. At a concentration of 0.75 mg MPA/l medium, all embryos showed dysmorphic changes. Embryos exposed to 0.25 mg MPA/l medium showed impaired development of nerves, and at 0.1 mg/l, no effects were detectable. Concentration-dependent ultrastructural changes, such as signs of apoptosis, were found by electron microscopy. The examination of the metabolite in this assay showed that at a concentration of 100 mg MPAG/l, the embryos exhibited distinct malformations. This is probably caused by MPA, which was detectable at 0.6 % in the material used for our experiments. The combination of the parent compound (0.03; 0.1; 0.25 mg/l) with its metabolite MPAG (3 mg/l) did not cause enhanced toxicity under our experimental conditions. IMPDH, the target enzyme of MPA, could be detected in rat embryos on day 9.5 of embryonic development as well as at the end of the culture period 48 h later. In summary, MPA impairs embryonic development at low, therapeutically relevant concentrations, but the glucuronide does not exhibit such a potential. Activity of MPA is not enhanced by MPAG.

Keywords: Mycophenolic acid; Mycophenolic acid glucuronide; Whole-embryo culture; Whole immunostaining; Inosine-5′-monophosphate dehydrogenase activity; Apoptosis

Chemical dispersant potentiates crude oil impacts on growth, reproduction, and gene expression in Caenorhabditis elegans by Yanqiong Zhang; Dongliang Chen; Adrien C. Ennis; Joseph R. Polli; Peng Xiao; Baohong Zhang; Edmund J. Stellwag; Anthony Overton; Xiaoping Pan (pp. 371-382).

The economic, environmental, and human health impacts of the deepwater horizon (DWH) oil spill have been of significant concern in the general public and among scientists. This study employs parallel experiments to test the effects of crude oil from the DWH oil well, chemical dispersant Corexit 9500A, and dispersant-oil mixture on growth and reproduction in the model organism Caenorhabditis elegans. Both the crude oil and the dispersant significantly inhibited the reproduction of C. elegans. Dose-dependent inhibitions of hatched larvae production were observed in worms exposed to both crude oil and dispersant. Importantly, the chemical dispersant Corexit 9500A potentiated crude oil effects; dispersant-oil mixture induced more significant effects than oil or dispersant-alone exposures. While oil-alone exposure and dispersant-alone exposure have none to moderate inhibitory effects on hatched larvae production, respectively, the mixture of dispersant and oil induced much more significant inhibition of offspring production. The production of hatched larvae was almost completely inhibited by several high concentrations of the dispersant-oil mixture. This suggests a sensitive bioassay for future investigation of oil/dispersant impacts on organisms. We also investigated the effects of crude oil/dispersant exposure at the molecular level by measuring the expressions of 31 functional genes. Results showed that the dispersant and the dispersant-oil mixture induced aberrant expressions of 12 protein-coding genes (cat-4, trxr-2, sdhb-1, lev-8, lin-39, unc-115, prdx-3, sod-1, acr-16, ric-3, unc-68, and acr-8). These 12 genes are associated with a variety of biological processes, including egg-laying, oxidative stress, muscle contraction, and neurological functions. In summary, the toxicity potentiating effect of chemical dispersant must be taken into consideration in future crude oil cleanup applications.

Keywords: Deepwater horizon (DWH) oil spill; C. elegans ; Toxicity; Growth; Reproduction; Gene expression

Nrf2-mediated redox signaling in arsenic carcinogenesis: a review by Dona Sinha; Jaydip Biswas; Anupam Bishayee (pp. 383-396).

Arsenic is a ubiquitous toxic metalloid whose natural leaching from geogenic resources of earths crust into groundwater has become a dreadful health hazard to millions of people across the globe. Arsenic has been documented as a top most potent human carcinogen by Agency of Toxic Substances and Disease Registry. There have been a number of schools of opinions regarding the underlying mechanism of arsenic-induced carcinogenicity, but the theory of oxidative stress generated by arsenic has gained much importance. Imbalance in the cellular redox state and its associated complications have been closely associated with nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic-leucine zipper transcription factor that activates the antioxidant responsive element and electrophilic responsive element, thereby upregulating the expression of a variety of downstream genes. This review has been framed on the lines of differential molecular responses of Nrf2 on arsenic exposure as well as the chemopreventive strategy which may be improvised to regulate Nrf2 in order to combat arsenic-induced oxidative stress and its long-term carcinogenic effect.

Keywords: Arsenic; Carcinogenicity; Chemoprevention; Nrf2; Oxidative stress

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