Turmeric, derived from the plant Curcuma longa, is a gold-colored spice commonly used in the Indian subcontinent, not only for health care but also for the preservation of food and as a yellow dye for textiles. Curcumin, which gives the yellow color to turmeric, was first isolated almost two centuries ago, and its structure as diferuloylmethane was determined in 1910. Since the time of Ayurveda (1900 Bc) numerous therapeutic activities have been assigned to turmeric for a wide variety of diseases and conditions, including those of the skin, pulmonary, and gastrointestinal systems, aches, pains, wounds, sprains, and liver disorders. Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin. Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, and anticancer activities and thus has a potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses. These effects are mediated through the regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other enzymes. Curcumin exhibits activities similar to recently discovered tumor necrosis factor blockers (e.g., HUMIRA, REMICADE, and ENBREL), a vascular endothelial cell growth factor blocker (e.g., AVASTIN), human epidermal growth factor receptor blockers (e.g., ERBITUX, ERLOTINIB, and GEFTINIB), and a HER2 blocker (e.g., HERCEPTIN). Considering the recent scientific bandwagon that multitargeted therapy is better than monotargeted therapy for most diseases, curcumin can be considered an ideal "Spice for Life".

Curcumin: The Indian solid gold

This public health statement tells you about chromium and the effects of exposure to it.The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term federal clean-up activities. Chromium has been found in at least 1,127 of the 1,699 current or former NPL sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility exists that the number of sites at which chromium is found may increase in the future as more sites are evaluated. This information is important because these sites may be sources of exposure and exposure to this substance may be harmful.When a substance is released either from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking the substance, or by skin contact.If you are exposed to chromium, many factors will determine whether you will be harmed. These factors include the dose (how much), the duration (how long), the form (chromium VI as opposed to chromium III), and how you come in contact with it. You must also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and state of health.

Toxicological Profile for Chromium

A new look at biomedical Ti-based shape memory alloys

Certain hexavalent chromium (Cr(VI))-containing compounds are recognized occupational human lung carcinogens and may pose an environmental health risk. The carcinogenicity of Cr(VI) is targeted to particulate forms of moderate to low solubility. Soluble Cr(VI) oxyanions in the immediate cellular microenvironment traverse the cell membrane by non-specific anionic transporters. Cr(VI) is reductively metabolized within cells by agents including ascorbic acid (Asc), glutathione (GSH) and cysteine (Cys). During Cr(VI) reduction, a diverse range of genetic lesions are generated including Cr-DNA binary (mono) adducts, Cr-DNA ternary adducts, DNA protein crosslinks (DPCs), bi-functional (DNA interstrand crosslinks (ICLs)) adducts, single-strand breaks (SSBs) and oxidized bases. Some forms of Cr damage, such as ICLs, present physical barriers to DNA replication/transcription and, thus, likely promote a terminal cell fate such as apoptosis or terminal growth arrest. Other lesions, such as ternary DNA adducts, are potentially pre-mutagenic. Cr(VI) exposure elicits a classical DNA damage response within cells including activation of the p53 signaling pathway and cell cycle arrest or apoptosis. Moreover, Cr(VI) also induces the ATM-dependent DNA damage response pathway which is paradoxically required for both apoptosis and survival after Cr(VI) insult. In yeast, moderately cytotoxic concentrations of Cr(VI) result in an initial G1 arrest and delayed S phase progression, whereas less toxic levels of Cr(VI) induce G2 arrest, which requires homologous recombination for exit and survival. The past several years has witnessed many important advances in our understanding of the genetic/cellular damage produced by exposure to Cr(VI). Further information is needed regarding the potential involvement of oxygen radicals in Cr genotoxicity, the specific DNA repair pathways activated by Cr and the complex signaling mechanisms involved in the cellular response to Cr(VI). These pertinent issues must be considered in relation to the potential role that each plays in the induction of human respiratory tract cancer by particulate Cr(VI) compounds.

Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms.

Cytotoxicity of metals is important because some metals are potential mutagens able to induce tumors in humans and experimental animals. Chromium can damage DNA in several ways, including DNA double strand breaks (DSBs) which generate chromosomal aberrations, micronucleus formation, sister chromatid exchange, formation of DNA adducts and alterations in DNA replication and transcription. In our study, water samples from three sites in the Corrego dos Bagres stream in the Franca municipality of the Brazilian state of Sao Paulo were subjected to the comet assay and micronucleus test using erythrocytes from the fish Oreochromis niloticus. Nuclear abnormalities of the erythrocytes included blebbed, notched and lobed nuclei, probably due to genotoxic chromium compounds. The greatest comet assay damage occurred with water from a chromium-containing tannery effluent discharge site, supporting the hypothesis that chromium residues can be genotoxic. The mutagenicity of the water samples was assessed using the onion root-tip cell assay, the most frequent chromosomal abnormalities observed being: c-metaphases, stick chromosome, chromosome breaks and losses, bridged anaphases, multipolar anaphases, and micronucleated and binucleated cells. Onion root-tip cell mutagenicity was highest for water samples containing the highest levels of chromium.

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Genotoxicity and mutagenicity of water contaminated with tannery effluents, as evaluated by the micronucleus test and comet assay using the fish Oreochromis niloticus and chromosome aberrations in onion root-tips

Chromium can be found in the environment in two main valence states: hexavalent (Cr(VI)) and trivalent (Cr(III)). Cr(VI) salts are well known human carcinogens, but the results from in vitro studies are often conflicting. Cr(VI) primarily enters the cells and undergoes metabolic reduction; however, the ultimate product of this reduction, Cr(III) predominates within the cell. In the present work, we compared the effects of tri- and hexavalent chromium on the DNA damage and repair in human lymphocytes using the alkaline single cell gel electrophoresis (comet assay). Potassium dichromate induced DNA damage in the lymphocytes, measured as the increase in comet tail moment. The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Cr(III) caused greater DNA migration than Cr(VI). The lymphocytes did not show measurable DNA repair. Vitamin C at 50 μM reduced the extent of DNA migration. This was either due to a decrease in DNA strand breaks and/or alkali labile sites induced by Cr(VI) or to the formation of DNA crosslinks by Cr(VI) in the presence of vitamin C. Vitamin C, however, did not modify the effects of Cr(III). Catalase, an enzyme inactivating hydrogen peroxide, decreased the extent of DNA damage induced by Cr(VI) but not the one induced by Cr(III). Lymphocytes exposed to Cr(VI) and treated with endonuclease III, which recognizes oxidized pyrimidines, displayed greater extent of DNA damage than those not treated with the enzyme. Such an effect was not observed when Cr(III) was tested. The results obtained suggest that reactive oxygen species and hydrogen peroxide may be involved in the formation of DNA lesions by hexavalent chromium. The comet assay did not indicate the involvement of oxidative mechanisms in the DNA-damaging activity of trivalent chromium and we speculate that its binding to cellular ligands may play a role in its genotoxicity.

A comparison of the in vitro genotoxicity of tri- and hexavalent chromium.

Genotoxicity of anticancer drugs is of a special interest due to the risk of inducing secondary malignancies. Vitamin C (ascorbic acid) is a recognized antioxidant and, since human diet can be easily supplemented with vitamin C, it seems reasonable to check whether it can protect against DNA-damaging effects of antitumor drugs. In the present work the ability of vitamin C to modulate cytotoxic and genotoxic effects of a cisplatin analog, conjugate (NH3)2Pt(SeO3), in terms of cell viability, DNA damage and repair in human lymphocytes was examined using the trypan blue exclusion test and the alkaline comet assay, respectively. The conjugate evoked a concentration-dependent decrease in the cell viability, reaching nearly 50% at 250 microM. (NH3)2Pt(SeO3) at 1, 10 and 30 microM caused DNA strand breaks, measured as the increase in the comet tail moment of the lymphocytes. The treated cells were able to recover within a 30-min incubation in a drug-free medium at 37 degrees C. Vitamin C at 10 and 50 microM diminished the extent of DNA damage evoked by (NH3)2Pt(SeO3) but had no effect on the kinetics of DNA repair. The vitamin did not directly inactivate the conjugate. Lymphocytes treated with endonuclease III, which recognises oxidised pyrimidines, displayed a greater tail moment than those untreated with the enzyme, suggesting that the damages induced by the drug have, at least in part, an oxidative origin. Vitamin C can be considered a potential protective agent against side effects of antitumor drugs, but further research with both normal and cancer cells are needed to clarify this point.

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Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate.

The naturally occurring pigment curcumin, a major component of the spice turmeric, is reported to be a potent inhibitor of the initiation and promotion of many cancers. Due to its presence in the diet, one of its primary targets is the human gastric mucosa (GM) cells. Using the sensitive single cell electrophoresis method (comet assay), we found that curcumin at of 15, 25, and 50 microM caused DNA damage in GM cells and human peripheral blood lymphocytes. There was no difference between the extent of the damage in both types of cells. Damaged cells were able to recover within a period of 120 minutes. Our results indicate that curcumin may play a dual role in carcinogenesis.

Curcumin damages DNA in human gastric mucosa cells and lymphocytes.

Cisplatin is a widely used anticancer drug, but its application is limited due to severe side effects. To reduce these effects, many other platinum drugs have been synthesized. In the present work comparative analysis of the toxicity of cisplatin, oxoplatin, and a conjugate (NH(3))(2)Pt(SeO(3)) (Se-Pt) in terms of cell viability, DNA binding, and DNA damage and repair in human lymphocytes was performed using the Trypan blue exclusion test, atomic absorption spectroscopy, and the comet assay, respectively. Cisplatin and oxoplatin did not cause a significant change in the viability of the lymphocytes even at the highest used concentration (750 microM), but the conjugate dramatically diminished viability at 100 microM only about 60% of the lymphocytes were viable (P < 0.05), and at 750 microM, less than 20% (P < 0.001). Se-Pt bound to isolated DNA was about 100 times weaker than the remaining two compounds; the binding of cisplatin was about 30% stronger than oxoplatin. Cisplatin and oxoplatin formed crosslinks with DNA in lymphocytes, whereas the conjugate induced DNA strand breaks. The lesions evoked by cisplatin and oxoplatin were slowly removed, but damage induced by Se-Pt was not repaired after 5 h even at a drug concentration of 10 microM. Severe cytotoxic and genotoxic effects exerted by Se-Pt in normal human lymphocytes preclude its intravenous application in cancer therapy. Teratogenesis Carcinog. Mutagen. 20:119-131, 2000.

DNA damage and repair in human lymphocytes exposed to three anticancer platinum drugs.

Hexavalent chromium compounds are well-recognized carcinogens. They easily penetrate the cell membrane and are reduced inside the cell to their trivalent form, which is supposed to react directly with DNA. Chromium is present in some workplaces as well as in water resources and food chain, so it can interact with the mucosa of the gastrointestinal tract. In order to elucidate the genotoxic potency of chromium in human gastric mucosa (GM) cells, the DNA-damaging effect of potassium dichromate (K2Cr2O7) was investigated using alkaline single cell gel electrophoresis (comet assay). Biopsy samples were obtained during gastroscopy from macroscopically healthy tissue of the stomach. Parallel test with human peripheral blood lymphocytes was also performed. Both types of cells were incubated at 37 degrees C with 1.6 mM of K2Cr2O7 for 1 h and after washing, were placed in a chromium-free medium to examine DNA repair. Alkaline single cell gel electrophoresis (comet assay) was used to assess DNA damage and repair. Chromium introduced a damage to DNA both in the GM cells and lymphocytes. The effect induced by K2Cr2O7 in GM cells was comparable with that caused in the lymphocytes. Treated cells were able to recover within a 60-min incubation in a chromium-free medium at 37 degrees C. The results obtained indicate that hexavalent chromium compounds, which may be found in the diet, can interact directly with DNA of the mucosa of the stomach.

Genotoxicity of chromium in human gastric mucosa cells and peripheral blood lymphocytes evaluated by the single cell gel electrophoresis (comet assay).

Joanna Kowalik

Papers

A comparison of the in vitro genotoxicity of tri- and hexavalent chromium.

Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate.

Curcumin damages DNA in human gastric mucosa cells and lymphocytes.

DNA damage and repair in human lymphocytes exposed to three anticancer platinum drugs.

Genotoxicity of chromium in human gastric mucosa cells and peripheral blood lymphocytes evaluated by the single cell gel electrophoresis (comet assay).