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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrosodimethylamine (NDMA) is a potent carcinogen in a wide variety of animal species. In experimental animals, dimethylamine and nitrite, precursors of NDMA, are found in gastric fluid where the acidic conditions are suitable for formation of nitrosamines. In this study we measured the concentrations of mono-, di- and trimethylamine (MMA, DMA and TMA) in gastric fluid from humans, rats, dogs and ferrets, as well as in saliva, blood and urine from humans. Human gastric fluid contained 3.7 +/- 0.4 (SEM) nmol/ml MMA, 12.6 +/- 1.4 nmol/ml DMA and 2.0 +/- 0.4 nmol/ml TMA. MMA, DMA and TMA concentrations in human gastric fluid were similar to those present in human saliva and blood, but were much lower than those present in human urine. The concentrations of these amines in human gastric fluid were lower than those measured in gastric fluid from experimental animals. When we added sodium nitrite to human gastric fluid, NDMA was formed. We have shown that DMA is normally present in human gastric fluid, and that it can be nitrosated to form NDMA.
Carcinogenesis 1988 Jan
PMID:Mono-, di- and trimethylamine in human gastric fluid: potential substrates for nitrosodimethylamine formation. 333 43

A speciation technique for arsenic has been developed using an anion-exchange high-performance liquid chromatography/inductively coupled argon plasma mass spectrometer (HPLC/ICP MS). Under optimized conditions, eight arsenic species [arsenocholine, arsenobetaine, dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)), arsenite (As(III)), and arsenate (As(V))] can be separated with isocratic elution within 10 min. The detection limit of arsenic compounds was 0.14-0.33 microg/L. To validate the method, Standard Reference Material in freeze-dried urine, SRM-2670, containing both normal and elevated levels of arsenic was analyzed. The method was applied to determine arsenic species in urine samples from three arsenic-affected districts of West Bengal, India. Both DMA(III) and MMA(III) were detected directly (i.e., without any prechemical treatment) for the first time in the urine of some humans exposed to inorganic arsenic through their drinking water. Of 428 subjects, MMA(III) was found in 48% and DMA(III) in 72%. Our results indicate the following. (1) Since MMA(III) and DMA(III) are more toxic than inorganic arsenic, it is essential to re-evaluate the hypothesis that methylation is the detoxification pathway for inorganic arsenic. (2) Since MMA(V) reductase with glutathione (GSH) is responsible for conversion of MMA(V) to MMA(III) in vivo, is DMA(V) reductase with GSH responsible for conversion of DMA(V) to DMA(III) in vivo? (3) Since DMA(III) forms iron-dependent reactive oxygen species (ROS) which causes DNA damage in vivo, DMA(III) may be responsible for arsenic carcinogenesis in human.
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PMID:Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. 1130 25

Both dimethylarsinic acid (DMA(V)) and dimethylarsinous acid (DMA(III)) release iron from human liver ferritin (HLF) with or without the presence of ascorbic acid. With ascorbic acid the rate of iron release from HLF by DMA(V) was intermediate (3.37 nM/min, P<0.05) and by DMA(III) was much higher (16.3 nM/min, P<0.001). No pBR322 plasmid DNA damage was observed from in vitro exposure to arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylarsonous acid (MMA(III)) or DMA(V) alone. DNA damage was observed following DMA(III) exposure; coexposure to DMA(III) and HLF caused more DNA damage; considerably higher amounts of DNA damage was caused by coexposure of DMA(III), HLF and ascorbic acid. Diethylenetriaminepentaacetic acid (an iron chelator), significantly inhibited DNA damage. Addition of catalase (which can increase Fe(2+) concentrations) further increased the plasmid DNA damage. Iron-dependent DNA damage could be a mechanism of action of human arsenic carcinogenesis.
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PMID:Plasmid DNA damage caused by methylated arsenicals, ascorbic acid and human liver ferritin. 1207 9

Many modes of action for arsenic carcinogenesis have been proposed, but few theories have a substantial mass of supporting data. Three stronger theories of arsenic carcinogenesis are production of chromosomal abnormalities, promotion of carcinogenesis and oxidative stress. This article presents the oxidative stress theory along with some supporting experimental data. In the area of which arsenic species is causually active, recent data have suggested that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), have a great deal of biological activity. Some evidence now indicates that these trivalent, methylated, and relatively less ionizable arsenic metabolites may be unusually capable of interacting with cellular targets such as proteins and even DNA. Thus for inorganic arsenic, oxidative methylation followed by reduction to trivalency may be a activation, rather than a detoxification pathway. This would be particularly true for arsenate. In forming toxic and carcinogenic arsenic species, reduction from the pentavalent state to the trivalent state may be as or more important than methylation of arsenic.
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PMID:Oxidative stress as a possible mode of action for arsenic carcinogenesis. 1250 28

Even though a well-known human carcinogen the underlying mechanisms of arsenic carcinogenicity are still not fully understood. For arsenite, proposed mechanisms are the interference with DNA repair processes and an increase in reactive oxygen species. Even less is known about the genotoxic potentials of its methylated metabolites monomethylarsonous [MMA(III)] and dimethylarsinous [DMA(III)] acid, monomethylarsonic [MMA(V)] and dimethylarsinic [DMA(V)] acid. Within the present study we compared the induction of oxidative DNA damage by arsenite and its methylated metabolites in cultured human cells and in isolated PM2 DNA, by frequencies of DNA strand breaks and of lesions recognized by the bacterial formamidopyrimidine-DNA glycosylase (Fpg). Only DMA(III) (> or =10 micro M) generated DNA strand breaks in isolated PM2 DNA. In HeLa S3 cells, short-term incubations (0.5-3 h) with doses as low as 10 nM arsenite induced high frequencies of Fpg-sensitive sites, whereas the induction of oxidative DNA damage after 18 h incubation was rather low. With respect to the methylated metabolites, both trivalent and pentavalent metabolites showed a pronounced induction of Fpg-sensitive sites in the nanomolar or micromolar concentration range, respectively, which was present after both short-term and long-term incubations. Furthermore MMA(III) and DMA(V) generated DNA strand breaks in a concentration-dependent manner. Taken together our results show that very low physiologically relevant doses of arsenite and the methylated metabolites induce high levels of oxidative DNA damage in cultured human cells. Thus, biomethylation of inorganic arsenic may be involved in inorganic arsenic-induced genotoxicity/carcinogenicity.
Carcinogenesis 2003 May
PMID:Induction of oxidative DNA damage by arsenite and its trivalent and pentavalent methylated metabolites in cultured human cells and isolated DNA. 1277 Oct 42

Previous research demonstrated that 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment increased the number of skin papillomas in v-Ha-ras transgenic (Tg.AC) mice that had received sodium arsenite [(As(III)] in drinking water, indicating that this model is useful for studying the toxic effects of arsenic in vivo. Because the liver is a known target of arsenic, we examined the pathophysiologic and molecular effects of inorganic and organic arsenical exposure on Tg.AC mouse liver in this study. Tg.AC mice were provided drinking water containing As(III), sodium arsenate [As(V)], monomethylarsonic acid [(MMA(V)], and 1,000 ppm dimethylarsinic acid [DMA(V)] at dosages of 150, 200, 1,500, or 1,000 ppm as arsenic, respectively, for 17 weeks. Control mice received unaltered water. Four weeks after initiation of arsenic treatment, TPA at a dose of 1.25 microg/200 microL acetone was applied twice a week for 2 weeks to the shaved dorsal skin of all mice, including the controls not receiving arsenic. In some cases arsenic exposure reduced body weight gain and caused mortality (including moribundity). Arsenical exposure resulted in a dose-dependent accumulation of arsenic in the liver that was unexpectedly independent of chemical species and produced hepatic global DNA hypomethylation. cDNA microarray and reverse transcriptase-polymerase chain reaction analysis revealed that all arsenicals altered the expression of numerous genes associated with toxicity and cancer. However, organic arsenicals [MMA(V) and DMA(V)] induced a pattern of gene expression dissimilar to that of inorganic arsenicals. In summary, subchronic exposure of Tg.AC mice to inorganic or organic arsenicals resulted in toxic manifestations, hepatic arsenic accumulation, global DNA hypomethylation, and numerous gene expression changes. These effects may play a role in arsenic-induced hepatotoxicity and carcinogenesis and may be of particular toxicologic relevance.
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PMID:Biokinetics and subchronic toxic effects of oral arsenite, arsenate, monomethylarsonic acid, and dimethylarsinic acid in v-Ha-ras transgenic (Tg.AC) mice. 1534 72

Epidemiological studies indicated that human arsenic exposure can induce urinary bladder cancer. Methylation of inorganic arsenic can generate more reactive and toxic organic arsenical species. In this regard, it was recently reported that the methylated arsenical metabolite, dimethylarsinic acid [DMA(V)], induced urinary bladder tumors in rats. However, other methylated metabolites, like monomethylarsonic acid [MMA(V)] and trimethylarsine oxide (TMAO) were not carcinogenic to the urinary bladder. In order to compare the early effects of DMA(V), MMA(V), and TMAO on the urinary bladder transitional cell epithelium at the scanning electron microscope (SEM) level, we investigated the sub-chronic (13 weeks) toxicological effects of MMA(V) (187 ppm), DMA(V) (184 ppm), TMAO (182 ppm) given in the drinking water to male and female F344 rats with a focus on the urinary bladder in this study. Obvious pathological changes, including ropy microridges, pitting, increased separation of epithelial cells, exfoliation, and necrosis, were found in the urinary bladders of both sexes, but particularly in females receiving carcinogenic doses of DMA(V). Urine arsenical metabolic differences were found between males and females, with levels of MMA(III), a potential genotoxic form, higher in females treated with DMA(V) than in males. Thus, this study provides clear evidence that DMA(V) is more toxic to the female urinary bladder, in accord with sensitivity to carcinogenesis. Important gender-related metabolic differences including enhanced presentation of MMA(III) to the urothelial cells might possibly account for heightened sensitivity in females. However, the potential carcinogenic effects of MMA(III) need to be further elucidated.
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PMID:A comparative study of the sub-chronic toxic effects of three organic arsenical compounds on the urothelium in F344 rats; gender-based differences in response. 1595 Sep 95

Inorganic arsenic is an environmental carcinogen. The generation of toxic trivalent methylated metabolites complicates the study of arsenic-mediated carcinogenesis. This study systematically evaluated the effect of chronic treatment with sodium arsenite (iAs(III)), monomethylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)) on immortalized human uroepithelial cells (SV-HUC-1 cells) using cDNA microarray. After exposure for 25 passages to iAs(III) (0.5 microM), MMA(III) (0.05, 0.1, or 0.2 microM), or DMA(III) (0.2 or 0.5 microM), significant compound-specific morphologic changes were observed. A set of 114 genes (5.7% of the examined genes) was differentially expressed in one or more sets of arsenical-treated cells compared with untreated controls. Expression analysis showed that exposure of cells to DMA(III) resulted in a gene profile different from that in cells exposed to iAs(III) or MMA(III), and that the iAs(III)-induced gene profile was closest to that in the tumorigenic HUC-1-derived 3-methylcholanthrene-induced tumorigenic cell line MC-SV-HUC T2, which was derived from SV-HUC-1 cells by methylcholanthrene treatment. Of the genes affected by all three arsenicals, only one, that coding for interleukin-1 receptor, type II, showed enhanced expression, a finding confirmed by the reduced increase in NF-kappaB (nuclear factor kappa B) activity seen in response to interleukin-1beta in iAs(III)-exposed cells. The expression of 11 genes was suppressed by all three arsenicals. 5-Aza-deoxycytidine partially restored the transcription of several suppressed genes, showing that epigenetic DNA methylation was probably involved in arsenical-induced gene repression. Our data demonstrate that chronic exposure to iAs(III), MMA(III), or DMA(III) has different epigenetic effects on urothelial cells and represses NF-kappaB activity.
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PMID:Distinct gene expression profiles in immortalized human urothelial cells exposed to inorganic arsenite and its methylated trivalent metabolites. 1650 63

Arsenicals have commonly been seen to induce reactive oxygen species (ROS) which can lead to DNA damage and oxidative stress. At low levels, arsenicals still induce the formation of ROS, leading to DNA damage and protein alterations. UROtsa cells, an immortalized human urothelial cell line, were used to study the effects of arsenicals on the human bladder, a site of arsenical bioconcentration and carcinogenesis. Biotransformation of As(III) by UROtsa cells has been shown to produce methylated species, namely monomethylarsonous acid [MMA(III)], which has been shown to be 20 times more cytotoxic. Confocal fluorescence images of UROtsa cells treated with arsenicals and the ROS sensing probe, DCFDA, showed an increase of intracellular ROS within five min after 1 microM and 10 microM As(III) treatments. In contrast, 50 and 500 nM MMA(III) required pretreatment for 30 min before inducing ROS. The increase in ROS was ameliorated by preincubation with either SOD or catalase. An interesting aspect of these ROS detection studies is the noticeable difference between concentrations of As(III) and MMA(III) used, further supporting the increased cytotoxicity of MMA(III), as well as the increased amount of time required for MMA(III) to cause oxidative stress. These arsenical-induced ROS produced oxidative DNA damage as evidenced by an increase in 8-hydroxyl-2'-deoxyguanosine (8-oxo-dG) with either 50 nM or 5 microM MMA(III) exposure. These findings provide support that MMA(III) cause a genotoxic response upon generation of ROS. Both As(III) and MMA(III) were also able to induce Hsp70 and MT protein levels above control, showing that the cells recognize the ROS and respond. As(III) rapidly induces the formation of ROS, possibly through it oxidation to As(V) and further metabolism to MMA(III)/(V). These studies provide evidence for a different mechanism of MMA(III) toxicity, one that MMA(III) first interacts with cellular components before an ROS response is generated, taking longer to produce the effect, but with more substantial harm to the cell.
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PMID:Arsenite and monomethylarsonous acid generate oxidative stress response in human bladder cell culture. 1693 Jun 58

Previous studies have shown that human bladder cells (UROtsa), a target of arsenic-induced cancer, can biotransform arsenite to monomethylarsonous acid (MMA(III)), which is more cytotoxic and capable of transforming the UROtsa cells following long-term, low-level exposure. Cyclooxygenase-2 (COX-2) causes hyperplasia in bladder cells and is considered a key biomarker in bladder cancer. To investigate the role of mitogenic pathway stimulation in MMA(III)-induced transformation, UROtsa cells were treated with 50nM MMA(III) for 12, 24, or 52 weeks and analyzed by Western blot for COX-2 expression. Elevations in COX-2 expression were noted following chronic MMA(III) exposure, and this induction increased with duration of exposure, suggesting that COX-2 or the signal transduction pathways responsible for COX-2 protein expression may play a role in MMA(III)-induced transformation. Acute exposure studies found MMA(III) treatment (10, 50, and 100nM, 4 h) induced COX-2 in UROtsa cells with the lowest doses (10 and 50nM) causing the strongest induction. Using pharmacological inhibitors of various pathways, it was shown that epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK-1/-2), phosphoinositide 3-kinase (PI3K), and src were important in the induction of COX-2 by MMA(III). ERK-2 phosphorylation was verified by Western blot analysis with a peak at 15 min, and c-jun was translocated to the nucleus following 50nM MMA(III) treatment. To determine MMA(III) targets, receptors of the erythroblastosis oncogene family (ErbB) family were further investigated. Chronic MMA(III) exposure led to upregulation of the EGFR or ErbB1. Short-term MMA(III) treatment caused the phosphorylation of ErbB2 in its autophosphorylation site. To verify the importance of these signaling pathways to the growth of the MMA(III)-transformed UROtsa cells in soft agar, various inhibitors were used to block pathways and monitor cells growth. Pathways of importance in anchorage-independent growth of UROtsa cells chronically exposed to MMA(III) are src, PI3K, and COX-1 and -2. As COX-2 is an important mediator that contributes to carcinogenesis via promotion of cell proliferation, inhibition of cell death, induction of angiogenesis, and facilitation of invasion, and it is highly upregulated both acutely and chronically in the MMA(III)-transformed cells, it is likely that activation of the mitogen-activated protein kinase pathway and increased COX-2 expression is a plausible mechanism for MMA(III) bladder carcinogenesis.
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PMID:Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells: role in arsenic-induced carcinogenesis. 1709 6


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