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Query: UNIPROT:P06889 (Mol)
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Hexavalent chromium (Cr (VI)) is reduced intracellularly to Cr (V), Cr (IV) and Cr (III) by ascorbate (Asc), cysteine and glutathione (GSH). These metabolites induce a spectrum of genomic DNA damage resulting in the inhibition of DNA replication. Our previous studies have shown that treatment of DNA with Cr (III) or Cr (VI) plus Asc results in the formation of DNA-Cr-DNA crosslinks (Cr-DDC) and guanine-specific arrests of both prokaryotic and mammalian DNA polymerases. GSH not only acts as a reductant of Cr (VI) but also becomes crosslinked to DNA by Cr, thus, the focus of the present study was to examine the role of GSH in Cr-induced DNA damage and polymerase arrests. Co-incubation of Cr (III) with plasmid DNA in the presence of GSH led to the crosslinking of GSH to DNA. GSH co-treatment with Cr (III) also led to a decrease in the degree of Cr-induced DNA interstrand crosslinks relative to Cr (III) alone, without affecting total Cr DNA binding. DNA polymerase arrests were observed following treatment of DNA with Cr (III) alone, but were markedly reduced when GSH was added to the reaction mixture. Pre-formed polymerase-arresting lesions (Cr-DDC) were not removed by subsequent addition of GSH. Treatment of DNA with Cr (VI), in the presence of GSH, resulted in crosslinking of GSH to DNA, but failed to produce detectable DNA interstrand crosslinks or polymerase arrests. The inhibitory effect of GSH on Cr-induced polymerase arrest was further confirmed in human genomic DNA using quantitative PCR (QPCR) analysis. Treatment of genomic DNA with Cr (III) resulted in a marked inhibition of the amplification of a 1.6 kb target fragment of the p53 gene by Taq polymerase. This was almost completely prevented by co-treatment with GSH and Cr (III). These results indicate that Cr-induced DNA interstrand crosslinks, and not DNA-Cr-GSH crosslinks, are the principal lesions responsible for blocking DNA replication. Moreover, the formation of DNA-Cr-GSH crosslinks may actually preclude the formation of the polymerase arresting lesions.
Mol Cell Biochem 2001 Jun
PMID:Effects of glutathione on chromium-induced DNA crosslinking and DNA polymerase arrest. 1167 99

Well-documented evidence suggests that environmental and occupational exposure of toxic metals or metal-containing compounds can cause a number of human diseases, including inflammation and cancer, through DNA damage, protein modifications, or lipid peroxidation. This mini-review addresses the mechanisms of cell death induced by some carcinogenic metals, including arsenic (III), chromium (VI) and vanadium (V). A possible contribution of reactive oxygen species to metal-induced cell death is also discussed.
Mol Cell Biochem 2001 Jun
PMID:Cell apoptosis induced by carcinogenic metals. 1167

Epidemiological and animal studies suggest that several metals and metal-containing compounds are potent mutagens and carcinogens. These metals include chromium, arsenic, vanadium, and nickel. During the last two decades, chemical and cellular studies have contributed enormously to our understanding of the mechanisms of metal-induced pathophysiological processes. Although each of these metals is unique in its mechanism of action, some common signaling molecules, such as reactive oxygen species (ROS), may be shared by many of these carcinogenic metals. New techniques are now available to reveal the mechanisms of carcinogenesis in precise molecular terms. In this review, we focused our attentions on metal-induced signal transduction pathways leading to the activation of NF-kappaB, a transcription factor governing the expression of most early response genes involved in a number of human diseases.
Mol Cell Biochem 2001 Jun
PMID:Carcinogenic metals and NF-kappaB activation. 1167 98

Chromium (VI) compounds are widely recognized as human carcinogens. Extensive studies in vitro and in model systems indicate that the reactive intermediate, Cr (V), generated by cellular reduction of Cr (VI), is likely the candidate for the ultimate carcinogenic form of chromium compounds. Here we review our current understanding of the in vivo reduction of Cr (VI) and its related free radical generation. Our results demonstrate that Cr (V) is indeed generated from the reduction of Cr (VI) in vivo, and that Cr (V) thus formed can mediate the generation of free radicals. Cr (V) and its related free radicals are very likely to be involved in the mechanism of Cr (VI)-induced toxicity and carcinogenesis. These studies also illustrate that in vivo EPR spectroscopy and magnetic resonance imaging can be very useful and powerful tools for studying paramagnetic metal ions in chemical and biochemical reactions occurring in intact animals.
Mol Cell Biochem 2001 Jun
PMID:In vivo reduction of chromium (VI) and its related free radical generation. 1167 10

Lung cancers are significantly increased among workers exposed to chromate (Cr6+, Cr3+), chromium pigments (Cr6+) and chromium plating (Cr6+). Chromium lung burdens and cancer risk increase proportionately with duration of employment at long latencies. However, this epidemiologic information alone is insufficient in determining whether Cr6+ or Cr3+ are equally important in causing cancer. We have attempted to combine epidemiologic data with data from the Drosophila melanogaster somatic-mutation-recombination-test and from the in vitro electron-spin-resonance spectroscopy study to demonstrate that following somatic recombination plays a more important role than somatic mutation in chromium carcinogenesis. Cr4+ is more important than Cr5+ or Cr6+ in inducing somatic recombination while Cr6+ produces more and bigger clones than Cr4+ in somatic mutation. Cr3+ produces negative results in this fruit-fly wing-spot-assay. When the larvae and flies exposed to Cr6+ and Cr4+ are examined by ESR, only Cr5+ and Cr3+ are found. Thermodynamic parameters deltaE, deltaH, and deltaS are also estimated from these latter experiments to explain the relative importance of Cr6+, Cr4+, Cr3+ in chromium carcinogenesis among exposed industrial workers.
Mol Cell Biochem 2001 Jun
PMID:Combining Drosophila melanogaster somatic-mutation-recombination and electron-spin-resonance-spectroscopy data to interpret epidemiologic observations on chromium carcinogenicity. 1167 12

Chromium (Cr) is a trace element required for life. Biological activities of Cr are complicated and remain to be fully investigated. It is known that the valence of Cr plays an important role in the biological activities of Cr. For example, Cr (VI) is classified as a metal carcinogen, but Cr (III) is widely used as a nutritional supplement. Establishment of a gene expression profile for Cr-induced cellular response is necessary to facilitate investigation of the biological activities of Cr. In the present study, a large-scale gene expression analysis was conducted using RNA of human lung epithelial cells after in vitro exposure to Cr (VI). Utilizing high-density oligonucleotide arrays representing 2400 genes, we observed that expression of 150 genes was up-regulated, and that of 70 genes were down-regulated by Cr (VI). Functional analysis of these responsive genes led to an outline of potential biological activities of Cr in six aspects. The gene expression profile reveals that Cr may involves in redox stress, calcium mobilization, energy metabolism, protein synthesis, cell cycle regulation and carcinogenesis in the cell. The results provide a critical clue for understanding molecular mechanisms of the biological activities of Cr.
Mol Cell Biochem 2001 Jun
PMID:Gene expression profile in response to chromium-induced cell stress in A549 cells. 1167 1

Chromium(VI) [Cr(VI)] and cadmium (Cd) compounds are ubiquitous environmental carcinogens that have been associated with lung tumors and can induce apoptosis in various cell types. Three major mitogen-activation protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, have been shown to regulate apoptosis. In this study we explore the abilities of Cr(VI) and Cd to activate JNK, p38 and ERK, including their roles in metal-mediated growth inhibition and apoptosis in a human non-small-cell lung carcinoma cell line, CL3. Exposure to K2Cr2O7 markedly activated JNK and p38 and moderately activated ERK in a dose- and time-dependent manner. The activated p38 decreased markedly and rapidly and the activated JNK decreased gradually when Cr(VI) was removed from media. At low cytotoxic doses, CdCl2 decreased ERK activity with concurrently transient activation of JNK, whereas at high cytotoxic doses it persistently activated all three MAPKs. The strength and duration of JNK and p38 activated by Cd were higher and longer than Cr(VI) did when compared at similar cytotoxic doses. In comparable experiment conditions Cd is a much stronger apoptotic inducer than Cr(VI) in CL3 cells. Cross-talk of MAPKs was observed in cells exposed to Cr(VI) but not Cd. Both metals could increase JNK activity through MKK7 but not MKK4. The Cd-activated JNK is involved in apoptosis, but the Cr-activated JNK is not. PD98059, an inhibitor of the ERK upstream activators MKK1/2, greatly enhanced the cytotoxicity and apoptosis of cells treated with low Cd doses. SB202190, an inhibitor of p38, decreased the cytotoxicity and apoptosis induced by high Cd doses. Conversely, neither SB202190 nor PD98059 altered Cr(VI)-induced cytotoxicity. The results suggest that JNK and p38 signals cooperatively participate in apoptosis induced by Cd and that the decreased ERK signal by low Cd doses contributes to growth inhibition or apoptosis. Oppositely, activation of ERK, JNK and p38 by Cr(VI) does not affect cytotoxicity.
Mol Cell Biochem 2001 Jun
PMID:Comparison of roles of three mitogen-activated protein kinases induced by chromium(VI) and cadmium in non-small-cell lung carcinoma cells. 1167 15

Progressive insulin resistance may contribute to both enhanced glycosylation of proteins and nucleic acids and augmented free radical damage commonly associated with aging. Accordingly, ingestion of chromium and antioxidants which improve insulin sensitivity and/or lessen free radical formation could theoretically ameliorate these basic disorders and lessen signs and symptoms of chronic age-related disorders. However, this supposition is based primarily upon acute rather than chronic data. Therefore, we divided 104 F344/BN rats into 2 groups: a control group receiving a basic diet and a test group receiving the same diet with added chromium polynicotinate (5 ppm), zinc monomethionine (18 ppm elemental zinc), and a grape seed extract high in flavonoids (250 ppm). Initial mean systolic blood pressures (SBP) of both control and test groups were 122 mm Hg. Over the first 7 months, the SBP of the control animals steadily increased to 140 mm Hg and remained at this level for the next 7-8 months. In contrast, the SBP of the test animals initially decreased over the first 4 months to as low as 110-114 mm Hg. The SBP then increased over the following months, essentially reaching the starting value of 120 mm Hg. This was still significantly lower than control (p < 0.001). In 12 control and 12 test rats, hepatic TBARS formation, an estimate of lipid peroxidation/free radical formation, was significantly lower after 1 year ingesting the test diet (p < 0.04); and HbA1C was also statistically significantly lower in the test group (5.4 vs. 4.8%, p < 0.003). Circulating levels of cholesterol, HDL, and triglycerides were similar between the two groups. Body, kidney, and liver weights were not different after 1 year ingesting the different diets; but epididymal fat pad weight was less in the group receiving supplements. We conclude that after prolonged supplementation a combination of agents known to sensitize insulin response and act as antioxidants (chromium polynicotinate, grape seed extract, and zinc monomethionine) can markedly lower SBP in normotensive rats, lessen oxidative damage to fats as suggested by decreased TBARS formation, and lower HbA1C without showing signs of toxicity.
Mol Cell Biochem 2001 Jul
PMID:Long-term effects of chromium, grape seed extract, and zinc on various metabolic parameters of rats. 1168 27

Although chromium has been the most extensively investigated metal with respect to mutagenicity and carcinogenicity, its genetic effects in humans are only partly understood. Our previous study demonstrated that lung cancer from chromate-exposed workers infrequently (20%) displayed p53 gene mutations as well as a particular mutation pattern. In the present study, we examined the replication error (RER) and loss of heterozygosity (LOH) in 38 lung cancers from 28 chromate-exposed workers (chromate lung cancer group) and in 26 lung cancer patients without chromate exposure (non-chromate lung cancer group), using six microsatellite markers containing CA repeats: D3S647 (3p23), D3S966 (3p21.3), D3S1289 (3p21.1), D5S346 (5q21-q22), D9S161 (9p21), and TP53 (17p13.1). The RER phenotype was defined as the presence of microsatellite instability (MSI) at two or more loci. Thirty (78.9%) of 38 tumors in the chromate lung cancer group exhibited RER. In contrast, only four (15.4%) of 26 tumors in the non-chromate lung cancer group exhibited RER. The frequency of RER in the chromate lung cancer group was significantly higher than that in the non-chromate lung cancer group (P < 0.0001). By contrast, the frequency of LOH at 3p, 5q, 9p, and 17p loci in tumors with chromate exposure was not significantly different from that in tumors without chromate exposure. In the chromate lung cancer group, the period of chromate exposure in workers with RER (24.5 +/- 6.7 yr) was significantly longer than that in workers without RER (17.0 +/- 3.5 yr) (P = 0.0046). In addition, a longer period of chromate exposure was associated with a tendency toward a higher frequency of MSI. This finding suggests that MSI may play a role in chromium-induced carcinogenesis. In addition to our previous study of p53 mutations, the present findings suggest that the carcinogenic mechanism of chromate lung cancer may differ from that of non-chromate lung cancer.
Mol Carcinog 2002 Mar
PMID:Frequent microsatellite instability in lung cancer from chromate-exposed workers. 1187 Aug 83

Electrophilic complexes of iron and chromium which have been reported to react with proteins in solution have been reacted with hen-egg white lysozyme (HEWL) in both the solution and crystal phases under similar pH and buffer conditions. This work was carried out with a view to developing novel side-chain selective heavy metal derivatives for protein X-ray crystallographic studies. Reaction of HEWL with a tricarbonyldienyliron cation (1) in aqueous solution led to modification of the sole histidine residue with concurrent reversible modification of other protein residues. Reaction of (1) with crystalline HEWL showed no covalent binding and only a build up of a hydrolysis product in the water channels of the crystal was observed. Reactions with a series of tricarbonylarylchromium pyrylium salts (2) led to the formation of stable covalent HEWL derivatives in solution. Chromatographic and IR spectroscopic studies showed that binding took place specifically at the epsilon-amino group of lysine residues to give a series of mono- and di-substituted products. When crystals of HEWL were soaked with the chromium reagents covalent binding to some of the lysine residues was also observed. In contrast, HEWL crystals which had their lysine side chains disabled did not bind any of the chromium reagents.
Spectrochim Acta A Mol Biomol Spectrosc 2002 Mar 15
PMID:FT-IR observation of covalent labelling of lysozyme crystals by organometallic complexes of transition metals. 1194


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