Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects on mouse skin of varying doses of light from a high-voltage mercury lamp were compared to the alterations occurring after repeated light applications from a carbon-arc xenon sunlamp. A single dose of UV light at a carcinogenic wavelength caused necrosis and ulceration, followed by scarring, but failed to produce tumors. In the case of repeated small doses, the neoplastic response was predominantly epithelial, resulting in formation of papillomas and squamous cell carcinomas. Increasing the dose caused formation of fibromas and fibrosarcomas of the ear. However, repeated applications of UV light having a spectrum similar to sunlight failed to induce tumors. In these studies, only animals showing initially destructive lesions ultimately presented tumor formation, while the hyperplasia induced by UV irradiation showed no relationship to neoplastic transformation. The results emphasize the significance of dose and wavelength in evaluating effects of UV-light skin carcinogenesis.
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PMID:Cellular injury and cell proliferation in skin carcinogenesis by UV light. 123 2

The therapeutic history of sodium diethyldithiocarbamate (dithiocarb) is briefly reviewed. Dithiocarb was discovered serendipitously in our laboratory 35 years ago for the specific treatment of nickel carbonyl poisoning. Since that time, the therapeutic efficacy of dithiocarb has been reported for many disorders, including: nickel, cadmium, thallium, copper, and mercury poisonings, experimental nickel carcinogenesis, protection against radiation damage to bone marrow, treatment of candidiasis in experimental animals, hepatolenticular degeneration (Wilson's disease), systemic lupus erythematosis, and human immunodeficiency virus infection (HIV). It has been used as an antagonist to cisplatin and cyclophosphamide toxicities, and as an antidote to hepatotoxicity induced by chloroform, carbon tetrachloride, and halothane. Most recently, it has been observed that the progression of HIV-1 infection is inhibited by dithiocarb administered intravenously or orally to patients with acquired immunodeficiency syndrome (AIDS). Attention is directed to the interactions of divalent cations to viral infections and to metal chelators (e.g., dithiocarb) as potential antiviral agents.
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PMID:Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS. 184 85

Azo dyes are widely used in textile, printing, cosmetic, drug and food-processing industries. They are also used extensively in laboratories as either biological stains or pH indicators. The extent of such use is related to the degree of industrialization. Since intestinal cancer is more common in highly industrialized countries, a possible connection may exist between the increase in the number of cancer cases and the use of azo dyes. Azo dyes can be reduced to aromatic amines by the intestinal microflora. The mutagenicity of a number of azo dyes is reviewed in this paper. They include Trypan Blue, Ponceau 3R, Pinceau 2R, Methyl Red, Methyl Yellow, Methyl Orange, Lithol Red, Orange I, Orange II, 4-Phenylazo-Naphthylamine, Sudan I, Sudan IV, Acid Alizarin Violet N, Fast Garnet GBC, Allura Red, Ponceau SX, Sunset Yellow, Tartrazine, Citrus Red No. 2, Orange B, Yellow AB, Carmoisine, Mercury Orange, Ponceau S, Versatint Blue, Phenylazophenol, Evan's Blue and their degraded aromatic amines. The significance of azo reduction in the mutagenesis and carcinogenesis of azo dyes is discussed.
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PMID:The significance of azo-reduction in the mutagenesis and carcinogenesis of azo dyes. 633 90

Transcription factor IIIA (TFIIIA), a cysteine-rich regulatory protein, is the prototype for the largest known superfamily of eukaryotic transcription factors. Members of the TFIIIA superfamily contain Cys2His2 zinc finger domains responsible for nucleic acid binding. Xenobiotic metal ions, which lack known biological function, were previously used as probes for the structure and function of steroid hormone receptors which contain Cys2Cys2 zinc finger domains. Structural alterations in cysteine-rich regulatory proteins by such ions in vivo might potentiate carcinogenesis and other disease processes. In the present study cadmium and other xenobiotic metal ions were used to probe the structure and function of TFIIIA. The specific interaction of TFIIIA with the internal control region (ICR) of the 5S RNA gene, as assayed by DNase I protection, was inhibited by Cd2+ ion concentrations of > or = 0.1 microM. Aluminum ions were also found to inhibit the TFIIIA-5S RNA gene interaction, albeit at higher concentrations (> or = 5 microM). Inhibition by either metal ion was not readily reversible. Other xenobiotic metal ions, such as mercury or cesium, were not found to be inhibitory under these conditions. None of these ions at the concentrations used in this study affected the ability of DNase I to digest DNA or restriction enzymes to specifically cleave DNA. Preincubation of TFIIIA bound to 5S RNA with either Cd2+ or Al3+ resulted in subsequent DNA binding upon dilution and RNA removal, whereas preincubation of free TFIIIA with the metal ions resulted in inhibition of subsequent DNA binding. Because 5S rRNA also binds the TFIIIA zinc finger domains, these results indicate that the 5S RNA bound to TFIIIA protects the protein from metal inhibition and implicates the zinc fingers in the inhibition mechanism. The nature of the footprint inhibition indicates that the N-terminal fingers of TFIIIA are affected by the metal ions. Cd2+ and Al3+ ions also inhibited the ability of TFIIIA to bind complementary single-stranded DNA and promote renaturation, as measured by Tris-phosphate agarose gel electrophoresis. This gel assay is sensitive to DNA conformation and Al3+ ions were found to alter the conformation of single- and double-stranded DNA in this assay. The inhibition of TFIIIA function in vitro by xenobiotic metals offers new insights into the structure and function of TFIIIA and TFIIIA-type zinc finger proteins. Inhibition by Cd2+ occurs at much lower concentrations than previously observed with steroid hormone receptors and suggests that Cys2His2 zinc finger proteins may be especially sensitive to such agents in vivo.
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PMID:Inhibition of transcription factor IIIA-DNA interactions by xenobiotic metal ions. 860 Apr 61

There is growing evidence that micronutrient intake has a significant effect on the toxicity and carcinogenesis caused by various chemicals. This paper examines the effect of micronutrient status on the toxicity of four nonessential metals: cadmium, lead, mercury, and arsenic. Unfortunately, few studies have directly examined the effect of dietary deficiency or supplementation on metal toxicity. More commonly, the effect of dietary alteration must be deduced from the results of mechanistic studies. We have chosen to separate the effect of micronutrients on toxic metals into three classes: interaction between essential micronutrients and toxic metals during uptake, binding, and excretion; influence of micronutrients on the metabolism of toxic metals; and effect of micronutrients on secondary toxic effects of metals. Based on data from mechanistic studies, the ability of micronutrients to modulate the toxicity of metals is indisputable. Micronutrients interact with toxic metals at several points in the body: absorption and excretion of toxic metals; transport of metals in the body; binding to target proteins; metabolism and sequestration of toxic metals; and finally, in secondary mechanisms of toxicity such as oxidative stress. Therefore, people eating a diet deficient in micronutrients will be predisposed to toxicity from nonessential metals.
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PMID:Effects of micronutrients on metal toxicity. 953 14

Toxic doses of transition metals are capable of disturbing the natural oxidation/reduction balance in cells through various mechanisms stemming from their own complex redox reactions with endogenous oxidants and effects on cellular antioxidant systems. The resulting oxidative stress may damage redox-sensitive signaling molecules, such as NO, S-nitrosothiols, AP-1, NF-kappaB, IkappaB, p53, p21ras, and others, and thus derange the cell signaling and gene expression systems. This, in turn, may produce a variety of toxic effects, including carcinogenesis. Experimental support for the relevance of oxidative damage to the mechanisms of metal toxicity and carcinogenicity is particularly strong for two essential (but toxic when overdosed) metals--iron and copper-- and three well-established human metal carcinogens--nickel, chromium, and cadmium. However, along with more specific effects of toxic metals associated with their selective binding to particular cell constituents and affecting calcium signaling, oxidative damage seems to become important as well in explaining mechanisms of pathogenicity of other metals, such as lead, mercury, and arsenic.
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PMID:Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: a review. 1098 86

The trace element selenium is involved in the protection against damage caused by free radicals. Selenium prevents carcinogenesis and growth of neoplasms. However, the mechanism is insufficiently known. Furthermore, selenium interacts with mercury, thereby preventing toxic reactions to high doses of mercury. The intake of selenium and the desired minimum and maximum concentrations are described.
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PMID:[Selenium and mercury. (Un)healthy antagonism?]. 1192 53

Mercuric chloride is an inorganic compound that has been used in agriculture as a fungicide, in medicine as a topical antiseptic and disinfectant, and in chemistry as an intermediate in the production of other mercury compounds. The widespread use of mercury has resulted in increased levels of mercury in rivers and lakes. Mercuric chloride was evaluated in toxicity and carcinogenicity studies because of its extensive use and its occurrence as an environmental pollutant, and because of the lack of adequate long-term rodent studies. Toxicology and carcinogenesis studies were conducted by administering mercuric chloride (greater than 99% pure) in deionized water by gavage to groups of F344 rats or B6C3F1 mice for 16 days, 6 months, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537), in mouse lymphoma L5178Y cells, in Chinese hamster ovary cells, and in Drosophila melanogaster. 16-DAY STUDIES: Groups of five rats of each sex received 0, 1.25, 2.5, 5, 10, or 20 mg mercuric chloride/kg body weight and groups of five mice of each sex received 0, 5, 10, 20, 40, or 80 mg/kg in deionized water by gavage for 12 dose days. Two male rats in the 20 mg/kg group died in the first week, as did all male and four female mice from the 80 mg/kg group and one male mouse from the 40 mg/kg group. The final mean body weight of male rats receiving 20 mg/kg was 10% lower than that of the controls; the final mean body weight of 20 mg/kg females was 9% lower than that of the controls. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Absolute and relative kidney weights of male rats receiving 2.5 mg/kg or greater doses and of female rats administered 5 mg/kg or more were significantly greater than those of the controls. Absolute kidney weights of mice were significantly increased in all male dose groups and in the 40 mg/kg female dose group; relative kidney weights of dosed male and female mice were significantly greater than the controls. Analysis of kidney, liver, and brain tissues for mercury residues revealed that the highest mercury concentration was in the kidneys of rats and mice. Acute renal tubule nephropathy occurred in dosed rats and was slightly more severe in males than in females. Chemical-related lesions in mice included renal tubule necrosis, inflammation and necrosis of the forestomach, and necrosis of the glandular stomach. 6-MONTH STUDIES: Groups of 10 rats of each sex received 0, 0.312, 0.625, 1.25, 2.5, or 5 mg mercuric chloride/kg body weight in deionized water by gavage for 26 weeks. Groups of 10 mice of each sex received 0, 1.25, 2.5, 5, 10, or 20 mg/kg in deionized water by gavage for 26 weeks (males) or 27 weeks (females). No deaths related to mercuric chloride administration occurred in rats or mice. Mean body weight gains of male rats that received 5 mg/kg and all female rat dose groups that received 0.625 mg/kg or greater were significantly lower than the controls. The final mean body weight and body weight gain of male mice in the 20 mg/kg group were significantly lower than those of the controls; final mean body weights and body weight gains of other dosed male mice and all dosed female mice were similar to those of the controls. Absolute and relative kidney weights of all dosed male rats and of female rats that received 0.625 mg/kg or greater were significantly greater than those of the controls. In male mice, absolute kidney weights in the three highest dose groups were significantly increased; no biologically significant differences in organ weights occurred in female mice. Analysis of kidney, liver, and brain tissues for mercury residues revealed the highest mercury concentration in the kidneys of rats and mice. The severity of chronic nephropathy increased with dose in male rats. Cytoplasmic vacuolation of renal tubule epithelial cells was observed in male mice in the 5, 10, and 20 mg/kg groups. No histopathologic changes in female mice were related to chemical exposure. 2-YEAR STUDIES: Groups YEAR STUDIES: Groups of 60 rats of each sex received 0, 2.5, or 5 mg mercuric chloride/kg body weight and groups of 60 mice of each sex received 0, 5, or 10 mg/kg in deionized water by gavage 5 days per week for 2 years. The doses were based on decreased weight gains in rats receiving 10 and 20 mg/kg and the decreased weight in male mice receiving 40 mg/kg during the 16-day studies, and on the decreased weight gains and toxicity results seen in the 6-month studies. Increased absolute and relative kidney weights in rats and male mice in the 6-month studies and degenerative renal changes suggested that higher dose levels would result in inadequate survival rates for a 2-year study. 15-Month Interim Evaluations: Relative kidney weights were significantly increased in dosed rats and female mice. The severity of nephropathy was increased in male rats, but not in females. High-dose male and female rats had minimal to mild hyperplasia of the basal cell layer in the forestomach epithelium (diagnosed as acanthosis); this lesion was not found in control or low-dose rats. Male mice had an increased severity of vacuolation of the renal tubule epithelium; no chemical-related lesions occurred in the kidneys of females. The incidence of inflammation of the olfactory epithelium lining the nasal cavity increased in male and female high-dose mice. Survival, Body Weights, and Clinical Signs: Survival of dosed male rats was lower than that of the controls (26/50, 10/50, 5/50); survival of dosed female rats was similar to that of the controls (35/50, 28/49, 30/50). Although more than 60% of the mice in each dose group survived to study end, survival rates of high-dose male mice and dosed female mice were lower than those of the controls (males: 36/50, 36/50, 31/50; females: 41/50, 35/50, 31/50). The final mean body weights of high-dose male and female rats were 15% and 14% lower than controls, respectively. The mean body weight of low-dose female rats was generally similar to controls throughout the 2-year study; the mean body weight of low-dose male rats was similar to that of the control through week 89. In mice, mean body weights of all male and female dose groups were similar to those of the controls throughout the studies. Pathology Findings: Chronic nephropathy appeared to develop at an accelerated rate and led to decreased survival in both dosed male rat groups. Secondary effects of renal dysfunction in dosed male rats resulted in increased incidences of fibrous osteodystrophy of the bone, mineralization of various tissues, and parathyroid gland hyperplasia. Based on evaluations of single and step sections, the incidence of renal tubule hyperplasia was increased in high-dose male rats (control, 3/50; high-dose, 10/50), but the incidences of renal tubule adenoma in high-dose and control males were similar (4/50, 5/50). Renal tubule hyperplasia was also slightly increased in high-dose female rats (2/50, 5/50) and adenomas were seen in high-dose females, but not in controls (0/50, 2/50). Incidences of forestomach hyperplasia in rats were markedly increased in dosed males (3/49, 16/50, 35/50) and high-dose females (5/50, 5/49, 20/50). Squamous cell papillomas of the forestomach were found in 3 low-dose and 12 high-dose males and in 2 high-dose females. No squamous cell carcinomas were found. The incidence of thyroid follicular cell carcinoma was marginally increased in high-dose male rats (1/50, 2/50, 6/50). However, a corresponding increased incidence in follicular cell adenomas (1/50, 4/50, 0/50) or hyperplasia (2/50, 4/50, 2/50) in males did not occur, and the overall incidence of follicular cell neoplasms was not significantly increased (2/50, 6/50, 6/50). The incidence of nasal mucosa inflammation in male and female rats was increased in the high-dose groups (male: 9/50, 8/47, 18/50; female: 0/49, 5/49, 15/50) and may have been related to chemical administration. The incidences of mammary gland fibroadenomas were significantly decreased in dosed female rats (15/50, 5/48, 2/50). The incidence and severity of nephropathy were increased in dosed mice; secondary effects of renal dysfunction did not occur. Renal tubule hyperplasia was found in one control and two high-dose male mice. Two renal tubule adenomas and one renal tubule adenocarcinoma were seen in high-dose male mice. Additional step sections revealed focal hyperplasia in another control male; no additional renal tubule neoplasms were found in high-dose or control males. Proliferative lesions of the renal tubule epithelium were not found in female mice. The incidence of metaplasia of the olfactory epithelium increased with dose in male and female mice. No other biologically significant lesions were found. GENETIC TOXICOLOGY: Mercuric chloride was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9). Induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster did not occur when mercuric chloride was administered in feed or by injection. However, positive results were obtained in mutagenicity tests with mammalian cells. In the absence of S9, mercuric chloride induced trifluorothymidine resistance in mouse L5178Y cells and chromosomal aberrations in Chinese hamster ovary cells. In the Chinese hamster ovary cell test for induction of sister chromatid exchanges, mercuric chloride produced a negative response without S9 and a weakly positive response in the presence of S9. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of mercuric chloride in male F344 rats based on the increased incidence of squamous cell papillomas of the forestomach. Marginally increased incidences of thyroid follicular cell adenomas and carcinomas may have been related to mercuric chloride exposure. There was equivocal evidence of carcinogenic activity of mercuric chloride in female F344 rats based on two squamous cell papillomas of the forestomach. There was equivocal evidence of carcinogenic activity of mercuric chloride in male B6C3F1 mice based on the occurrences of two renal tubule adenomas and one renal tubule adenocarcinoma. There was no evidence of carcinogenic activity of mercuric chloride in female B6C3F1 mice receiving 5 or 10 mg/kg. Nonneoplastic lesions associated with exposure to mercuric chloride included increased severity of nephropathy in male rats and male and female mice. There was an increased incidence of renal tubule hyperplasia in male rats. The incidence of forestomach hyperplasia was increased in dosed male and female rats. Increased incidences of nasal mucosa inflammation were associated with mercuric chloride administration in rats. Increased incidences of olfactory epithelial metaplasia in mice were also associated with mercuric chloride administration. Synonyms: Abavit B, calochlor, corrosive sublimate, dichloromercury, mercuric bichloride, mercury chloride, mercury (II) chloride, mercury bichloride, mercury perchloride, sublimate, sulem, bichloride of mercury, corrosive mercury chloride, perchloride of mercury, mercury dichloride Trade name: Fungchex
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PMID:Toxicology and Carcinogenesis Studies of Mercuric Chloride (CAS No. 7487-94-7) in F344 Rats and B6C3F1 Mice (Gavage Studies). 1262 22

In many research groups including our laboratory, metallothionein (MT)-I/II null mice have been used to clarify the biological function and physiological role of MT. Recent studies with MT-I/II null mice concerning the role of MT in the toxicity and distribution of metal, oxidative stress and chemical carcinogenesis were reviewed. Some reports, including our findings, showed that MT-I/II null mice have an increased sensitivity to harmful metals such as cadmium, mercury, zinc and arsenic. Moreover, it was clarified using MT-I/II null mice that MT plays a major role in the retention of cadmium, mercury and zinc in target tissues. MT-I/II null mice were found to be much more sensitive than wild-type mice to the toxicity caused by free radical-inducing factors, which include paraquat, acetaminophen, ethanol, X-ray, ultraviolet B, carbon tetrachloride, cisplatin, doxorubicin, cerulein and streptozotocin. In addition, MT-I/II null mice were highly susceptible to skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene and bladder carcinogenesis caused by N-butyl-N-(4-hydroxybutyl)nitrosamine. These results suggest that MT is an important protective factor against metal toxicity, oxidative stress and chemical carcinogenesis.
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PMID:[Toxicological significance of metallothionein on environmental harmful factors: verification and suggestions from a metallothionein-I/II null mouse model study]. 1535 96

When exposed to UVR, MRC5 fibroblasts incubated with mercuric chloride (0-15 microM) for 1 hour show increased DNA damage (as measured by the comet assay) compared to control cells (UVR irradiated but no mercuric chloride). This demonstrates that mercuric chloride and UVR in combination increase DNA damage in a synergistic manner. This may have implications to those exposed to mercury as it suggests that exposure to mercury in the environment may increase sensitivity to sunlight-induced carcinogenesis.
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PMID:Hg(II) exposure exacerbates UV-induced DNA damage in MRC5 fibroblasts: a comet assay study. 1642 20


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