Identification of the Multifaceted Chemopreventive Activity of Curcumin Against the Carcinogenic Potential of the Food Additive, KBrO3.

BACKGROUND: Potassium bromate (KBrO3), a food additive, has been used in many bakery products as an oxidizing agent. It has been shown to induce renal cancer in many in-vitro and in-vivo experimental models. OBJECTIVES: This study evaluated the carcinogenic potential of potassium bromate (KBrO3) and the chemopreventive mechanisms of the anti-oxidant and anti-inflammatory phytochemical, curcumin against KBrO3-induced carcinogenicity. METHOD: Lactate dehydrogenase (LDH) cytotoxicity assay and morphological characteristics were used to assess curcumin's cytoprotective potential against KBrO3 toxicity. To assess the chemopreventive potential of curcumin against KBrO3-induced oxidative insult, intracellular H2O2 and the nuclear concentration of the DNA adduct 8- OHdG were measured. PCR array, qRT-PCR, and western blot analysis were used to identify dysregulated genes by KBrO3 exposure. Furthermore, immunofluorescence was used to evaluate the ciliary loss and the disturbance of cellular tight junction induced by KBrO3. RESULTS: Oxidative stress assays showed that KBrO3 increased the levels of intracellular H2O2 and the DNA adduct 8-OHdG. Combination of curcumin with KBrO3 efficiently reduced the level of H2O2 and 8-OHdG while upregulating the expression of catalase. PCR array, qRT-PCR, and western blot analysis revealed that KBrO3 dysregulated multiple genes involved in inflammation, proliferation, and apoptosis, namely CTGF, IL-1, and TRAF3. Moreover, qRT-PCR and immunofluorescence studies showed that KBrO3 negatively affected the tight junctional protein (ZO-1) and induced a degeneration of primary ciliary proteins. The negative impact of KBrO3 on cilia was markedly repressed by curcumin. CONCLUSION: Curcumin could potentially be used as a protective agent against carcinogenicity of KBrO3.

A mushroom-derived amino acid, ergothioneine, is a potential inhibitor of inflammation-related DNA halogenation.

Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. In this study, we showed that ergothioneine (EGT), derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2'-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than those of ascorbic acid and glutathione. We initially observed that the administration of Coprinus comatus, an edible mushroom containing a high amount of EGT, inhibited the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.

A mineral and antioxidant-rich extract from the red marine Algae Alsidium corallinum exhibits cytoprotective effects against potassium bromate-induced erythrocyte oxidative damages in mice.

The present study was carried out to investigate potassium bromate toxicity in mice and the corrective effects of marine algae Alsidium corallinum. The red algae demonstrated its rich composition in phenols, triterpenes, flavonoids, alkaloids, tropolones, sodium, potassium, calcium, magnesium, iron, copper, and zinc. To confirm its antioxidant potential, an in vivo study was performed on adult mice. The animals were divided into four groups: group I were used as controls, group II received potassium bromate (0.5 g/L) via drinking water, group III received potassium bromate (0.5 g/L) by the same route as group II and 7% of A. corallinum ethanolic extract via their diet, and group IV received only 7% of algae. The potassium bromate-treated group showed a significant decrease in erythrocyte, platelet, hemoglobin, and hematocrit values and a significant increase in total white blood cells, compared to those of controls. While, superoxide dismutase, catalase, glutathione, and vitamin C values were decreased by potassium bromate treatment, lipid peroxidation (as malondialdehyde) and erythrocyte osmotic fragility values were increased. Interestingly, potassium bromate treatment showed significant genotoxic effects, as demonstrated by DNA degradation. These changes were confirmed by blood smears histopathological observations which were marked by a necrosis and a decrease of erythrocytes number. A. corallinum extract appeared to be effective against hematotoxic and genotoxic changes induced by potassium bromate, as evidenced by the improvement of the parameters cited above.

Melatonin restores the basal level of lipid peroxidation in rat tissues exposed to potassium bromate in vitro.

OBJECTIVE: Potassium bromate (KBrO3) is a prooxidant and carcinogen. Melatonin is a highly effective antioxidant. Indole-3-propionic acid (IPA; indole substance) and propylothiouracil (PTU; antithyroid drug) reveal some antioxidative effects. The aim of the study was to evaluate KBrO3-induced lipid peroxidation (LPO) in vitro in tissues collected from control or melatonin-treated rats, and to compare potential preventive effects of melatonin, IPA and PTU. MATERIALS AND METHODS: Kidney, liver and lung homogenates from either control or melatonin-pretreated rats (0.0645 mmol/kg b.w., i.p., twice daily, 10 days) were incubated in the presence of KBrO3 (0.1, 0.5, 1.0, 2.5, 5.0, 10.0 mM). Then, control lung homogenates were incubated with KBrO3 (10.0 mM) together with melatonin (0.01, 0.1, 0.5, 1.0, 5.0, 7.5 mM), or with IPA or with PTU. LPO products (malondialdehyde+4-hydroxyalkenals) were measured spectrophotometrically. RESULTS: Melatonin injections prevented KBrO3-induced LPO in lung homogenates. Melatonin, IPA and PTU, used in vitro, reduced KBrO3-induced LPO in control lungs. Unexpectedly, KBrO3 caused a concentration-dependent decrease in LPO in liver and kidney homogenates from control but not from melatonin-treated rats. CONCLUSIONS: Potassium bromate-induced LPO in the rat lung homogenates suggests that the lung may be the target for this carcinogen. An exposure of organisms to melatonin decreases tissue sensitivity to KBrO3-induced damage, possibly by restoring the oxidative balance.

Comparative efficacy of oligonol, catechin and (-)-epigallocatechin 3-O-gallate in modulating the potassium bromate-induced renal toxicity in rats.

Potassium bromate (KBrO(3)) is a by-product from ozonation of high-bromide surface water for production of drinking water and is a rodent carcinogen. Oligonol is a product emanating from the oligomerization of polyphenols, typically proanthocyanidin from a variety of fruits (grapes, apples, persimmons, etc.) and contains catechin-type monomers and proanthocyanidin oligomers. In this study, the ability of oligonol derived from grape seeds, grape seeds extracts (Product A, containing biologically active flavonoids and the oligomeric proanthocyanidin) and pine bark extracts (Product B, composed of flavan-3-ol derivatives) to modulate the KBrO(3)-induced renal toxicity was compared with (+) catechin and (-)-epigallocatechin 3-O-gallate (EGCG). In the Trolox equivalent antioxidant capacity (TEAC) assay, the order of the antioxidant activity was EGCG>catechin>oligonol>Product A>Product B. However, oligonol elicits the strongest antioxidant capacity following in vivo supplementation to rats, with the order of efficacy of oligonol>Product A> or =Product B>EGCG>catechin. Blood levels of lipid peroxidation products (LPO), urea nitrogen (BUN) and creatinine were elevated by KBrO(3) treatment. Oligonol significantly restored LPO to the level in the untreated rats and had the strongest potency when compared with the effects of Products A and B. The five materials lowered KBrO(3)-induced BUN level, but this was not statistically significant. Oligonol significantly reduced the increased level of the creatinine, seconded by Product A, Product B and EGCG. Catechin had the lowest effect in both the BUN and creatinine levels. That oligonol was able to modulate KBrO(3)-induced lipid peroxidation and the levels of blood urea nitrogen and creatinine suggests potential chemopreventive function and application in mitigating toxicity due to long-term exposure to KBrO(3) in public drinking water.

Modulatory effect of Ficus racemosa: diminution of potassium bromate-induced renal oxidative injury and cell proliferation response.

The aim of the present study was to determine the potential beneficial effects of Ficus racemosa extract. Potassium bromate (KBrO3), a potent nephrotoxic agent that induces renal carcinogenesis and acts as tumour promoter in carcinogen-initiated animals was used as a model to induce renal injury. In this study, we show the chemopreventive effect of Ficus racemosa extract (Moraceae) on KBrO3-mediated renal oxidative stress and cell promotion response in rats. KBrO3 (125 mg/kg body weight, intraperitoneally) enhanced lipid peroxidation, xanthine oxidase, gamma-glutamyl transpeptidase and hydrogen peroxide (H2O2) generation with reduction in renal glutathione content and antioxidant enzymes. KBrO3 treatment also induced tumour promotion markers, viz., ornithine decarboxylase activity and thymidine [3H] incorporation into renal DNA. A sharp elevation in the levels of blood urea nitrogen and serum creatinine has also been observed. Treatment of rats orally with Ficus racemosa extract (200 mg/kg body weight and 400 mg/kg body weight) resulted in a significant decrease in xanthine oxidase (P<0.05), lipid peroxidation (P<0.001), gamma-glutamyl transpeptidase (P<0.001) and H(2O2 (P<0.001). There was significant recovery of renal glutathione content (P<0.01) and antioxidant enzymes (P<0.001). There was also reversal in the enhancement of renal ornithine decarboxylase activity, DNA synthesis, blood urea nitrogen and serum creatinine (P<0.001). Our results suggest that Ficus racemosa extract is a potent chemopreventive agent and suppresses KBrO3-mediated nephrotoxicity in rats.

Inhibition of potassium bromate-induced renal oxidative stress and hyperproliferative response by Nymphaea alba in Wistar rats.

KBrO3-mediated renal injury and hyperproliferative response in Wistar rats. In this communication, we report the efficacy of Nymphaea alba on KBrO3 (125 mg/kg body weight, intraperitoneally) caused reduction in renal glutathione content, renal antioxidant enzymes and phase-II metabolising enzymes with enhancement in xanthine oxidase, lipid peroxidation, gamma-glutamyl transpeptidase and hydrogen peroxide (H202). It also induced blood urea nitrogen, serum creatinine and tumor promotion markers, viz., ornithine decarboxylase (ODC) activity and DNA synthesis. Treatment of rats with Nymphaea alba (100 and 200 mg/kg body weight) one hour before KBrO3 (125 mg/kg body weight, i.p.) resulted in significant decreases in xanthine oxidase (P < 0.05), lipid peroxidation, gamma-glutamyl transpeptidase, H202 generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content, glutathione metabolizing enzymes and antioxidant enzymes were also recovered to significant levels (P < 0.001). These results show that Nymphaea alba acts as chemopreventive agent against KBrO3-mediated renal injury and hyperproliferative response.

Abrogation of potassium bromate-induced renal oxidative stress and subsequent cell proliferation response by soy isoflavones in Wistar rats.

Potassium bromate (KBrO3) is a potent nephrotoxic agent. In this study, we show the modulatory effect of soy isoflavones on KBrO3-mediated renal oxidative stress and subsequent cell proliferation response in Wistar rats. KBrO3 (125 mg/kg body weight, intraperitoneally) caused reduction in renal glutathione content, activities of renal anti-oxidant enzymes, viz., glutathione peroxidase, glutathione reductase, catalase, glucose-6-phosphate dehydrogenase and phase-II metabolising enzymes such as glutathione-S-transferase and quinone reductase with enhancement in xanthine oxidase, lipid peroxidation, gamma-glutamyl transpeptidase and hydrogen peroxide (H2O2). KBrO3 treatment also induced blood urea nitrogen, serum creatinine and tumor promotion markers, viz., ornithine decarboxylase (ODC) activity and thymidine [3H] incorporation into renal DNA. Treatment of rats orally with soy isoflavones (5 mg/kg body weight and 10 mg/kg body weight) resulted in a significant decrease in xanthine oxidase (P < 0.05), lipid peroxidation, gamma-glutamyl transpeptidase, H2O2 generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). There was also significant recovery of renal glutathione content (P < 0.01), anti-oxidant enzymes and phase-II metabolising enzymes (P < 0.001). Thus, our results show that soy isoflavones acts as potent chemopreventive agent against KBrO3-mediated renal oxidative stress, toxicity and subsequent cell proliferation response in Wistar rats.

Attenuation of potassium bromate-induced nephrotoxicity by coumarin (1,2-benzopyrone) in Wistar rats: chemoprevention against free radical-mediated renal oxidative stress and tumor promotion response.

We report the modulatory effect of coumarin (1,2-benzopyrone) on potassium bromate (KBrO(3)) mediated nephrotoxicity in Wistar rats. KBrO(3) (125 mg/kg body weight, i.p.) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H(2)O(2)) generation with reduction in renal glutathione content and antioxidant enzymes. It also enhances blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and [(3)H]-thymidine incorporation into renal DNA. Treatment of rats orally with coumarin (10 mg/kg body weight and 20 mg/kg body weight) resulted in a significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H(2)O(2) generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01) and antioxidant enzymes were also recovered to significant level (P < 0.001). These results show that coumarin may be used as an effective chemopreventive agent against KBrO(3)-mediated renal oxidative stress, toxicity and tumor promotion response in Wistar rats.

Kinetic spectrophotometric determination of thiocyanate based on its inhibitory effect on the oxidation of methyl red by bromate.

A kinetic spectrophotometric method for measuring thiocyanate is described. The proposed method is based on the inhibitory effect of thiocyanate on the oxidation of Methyl Red by bromate in the presence of nitrite, which was monitored at 520 nm. The variables affecting the rate of the reaction were investigated and the optimum conditions were established. Thiocyanate can be measured in the range of 0.05-1.1 microg ml(-1) with a detection limit of 0.025 microg ml(-1). This method has been used to determine trace thiocyanate in urine and tap water samples.