Arsenic toxicity

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Arsenic toxicity
Classification and external resources
ICD-10 T57.0
ICD-9 985.1

Arsenic and many of its compounds are especially potent poisons. Arsenic disrupts ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure (see arsenic poisoning) probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role.[1]

Exposure[edit]

The oxides of arsenic are the most common threat since arsenite and arsenate salts are the most toxic. These forms are components of geologic formations and are extracted into the ground water. Thus although arsenic poisoning can be related to human activities such as mining and ore smelting, the most serious problems are natural, resulting from water wells drilled into aquifers that have high concentrations of arsenic. "Inorganic arsenic" (arsenate and arsenite salts) are more harmful than organic arsenic exposure.[2]

Organic arsenic is 500 times less harmful than inorganic arsenic,[3] and is a minor problem compared to the groundwater situation which affects many millions of people. Seafood is a common source of the less toxic organic arsenic in the form of arsenobetaine. The arsenic reported in 2012 in fruit juice and rice by Consumer Reports was primarily inorganic arsenic.[4][5] Persistent contact to arsenic is linked with a broad variety of neurologic, cardiovascular, dermatologic, and carcinogenic effects; including peripheral neuropathy, diabetes, ischemic heart disease, melanosis, keratosis, and impairment of liver function.[6]

Kinetics[edit]

The two forms of inorganic arsenic, reduced (trivalent As (III)) and oxidized (pentavalent As(V)), can be absorbed, and accumulated in tissues and body fluids.[7] In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation, the most frequently excreted metabolite (≥ 90%) in the urine of mammals is dimethylarsinic acid(or Cacodylic acid) (DMA(V)).[8] Dimethylarsenic acid is also known as Agent Blue and was used as herbicide in the American war in the South-East Asian country of Viet Nam.

In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione (GSH) or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bio availability, Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell.[9] Resulting metabolites are monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)).

Methylation had been regarded as a detoxification process,[by whom?] but reduction from +5 As to +3 As may be considered as a bioactivation[clarification needed] instead.[10] Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent arsenics.[9] Gebel (2002) stated that methylation is a detoxification through accelerated excretion.[11] With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.[12][13][14]

Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacts with a variety of proteins and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification.[15] Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase[16] and thioredoxin reductase.[17]

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers.[8] Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues.[8]

Mechanism[edit]

Arsenite inhibits not only the formation of Acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-Arsenate in vitro; therefore it has been argued that hexokinase could be inhibited.[18] (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde-3-P-dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in Glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis) As shown by Gresser (1981), submitochondrial particles synthesize Adenosine-5’-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation.[19] This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.

Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2] and adhesion proteins in platelets, while human platelets showed similar responses.[20] The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide. It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.[21]

Carcinogenicity[edit]

It is still a matter of debate whether DNA repair inhibition or alterations in the status of DNA methylation are responsible for the carcinogenic potential of As. As vicinal sulfhydryl groups are frequently found in DNA-binding proteins, transcription factors and DNA-repair proteins, interaction of arsenic with these molecules appears to be likely. However, in vitro, most purified DNA repair enzymes are rather insensitive to arsenic, but in cell culture, As produces a dose-dependent decrease of DNA ligase activity. This might indicate that inhibition of DNA repair is an indirect effect due to changes in cellular redox levels or altered signal transduction and consequent gene expression.[22] In spite of its carcinogenicity, the potential of arsenic to induce point mutations is weak. If administered with point mutagens it enhances the frequency of mutations in a synergistic way.[23]

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures.[24] DMA showed to effectuate DNA single stand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.[25][26]

+3 MMA and +3 DMA were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA.[27] Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations,[28] micronuclei[29][30] and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.[31]

+3 DMA is able to form reactive oxygen species (ROS) by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.[32] Both +5 DMA and +3 DMA were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of ROS can be promoted.[33] Moreover, arsenic could cause oxidative stress by depleting the cell’s antioxidants, especially the ones containing thiol groups. The accumulation of ROS like the cited above and hydroxyl radicals, superoxide radicals and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins and DNA in higher concentrations which eventually lead to cellular death. In a rat animal model, urine levels of 8-hydroxy-2’-desoxyguanosine (as a biomarker of ROS DNA damage) were measured after treatment with DMA. In comparison to control levels, they turned out to be significantly increased.[34] This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides (LPO) in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood.[35] Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants.[36] A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory provides an explanation for the preferred tumor sites connected with arsenic exposure.[12] Considering that a high partial pressure of oxygen is present in lungs and +3 DMA is excreted in gaseous state via the lungs this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys and latter on stored in the bladder accounts for the other tumor localizations.

Regarding DNA methylation, some studies suggest interaction of As with methyltransferases which leads to an inactivation of tumor suppressor genes through hypermethylation, others state that hypomethylation might occur due to a lack of SAM resulting in aberrant gene activation.[37] An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed PCR.[38] It turned out that six of the fragments were hyper- and two of them were hypomethylated.[38] Higher levels of DNA methltransferase mRNA and enzyme activity were found.[38]

Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to carcinogenesis.[12] From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity.[23][39] MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux.[40] The efflux requires GSH, but no As-GSH complex formation.[41]

Although many mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. Current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling.[42]

Heat shock response[edit]

Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27,60,70,72,90,110 kDa as well as metallotionein, ubiquitin, mitogen-activated [MAP] kinases, extracellular regulated kinase [ERK], c-jun terminal kinases [JNK] and p38.[31][43] Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines[31][44][45] The effects are largely dependant on the dosing regime and may be as well inversed.

As shown by some experiments reviewed by Del Razo (2001), ROS induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation.[43][46] Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.[47]

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.[48] Thus, taking into account p53’s function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result.[49] The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis.[49] As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction which is not clearly understood yet.[citation needed]

Oxidative stress[edit]

Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPAR’s, AP-1, and NF-κB,[8][49][50] as well as the pro-inflammatory cytokines IL-8 and TNF-α.[8][49][50][51][52][53][54][55] The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity, insulin resistance, inflammation, and diabetes-2.[56][57][58] Recent scientific evidence has elucidated the physiological roles of the PPAR’s in the ω- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-κB and AP-1), pro-inflammatory cytokines (IL-1, -6, -8, -12, and TNF-α), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors.[8][51][56][58][59]

Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of Type 2-diabetes.[8] The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis.[8] However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.[8]

See also[edit]

References[edit]

  1. ^ Klaassen, Curtis; Watkins, John (2003). Casarett and Doull's Essentials of Toxicology. McGraw-Hill. p. 512. ISBN 978-0-07-138914-3. 
  2. ^ P.L. Smedley, D.G. Kinniburgh, D.M.J. Macdonald, H.B. Nicolli, A.J. Barros, J.O. Tullio, J.M. Pearce, M.S. Alonso "Arsenic associations in sediments from the loess aquifer of La Pampa, Argentina" Applied Geochemistry 20 (2005) 989–1016. doi:10.1016/j.apgeochem.2004.10.005
  3. ^ Medicine net.com july,2 2010 definition of arsenic
  4. ^ "Arsenic in your food: Our findings show a real need for federal standards for this toxin". Consumer Reports. November 2012. Retrieved 22 November 2012. 
  5. ^ EFSA Panel on Contaminants in the Food Chain (CONTAM) (22 October 2009). "Scientific Opinion on Arsenic in Food". EFSA Journal (European Food Safety Authority) 7 (10): 1351. doi:10.2903/j.efsa.2009.1351. Retrieved 22 November 2012. 
  6. ^ Roy, Debarshi; Gaur, Priya; Verma, Neeraj; Pathireddy, Monika; Singh, Krishna.P. (2013). "Bioremediation of Arsenic (III) from Water Using Baker Yeast Sacchromyces cerevisiae.". International Journal of Environmental Bioremediation & Biodegradation 1: 14–19. doi:10.12691/ijebb-1-1-3. 
  7. ^ Ueki K, Kondo T, Tseng YH, Kahn CR (July 2004). "Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse". Proceedings of the National Academy of Sciences of the United States of America 101 (28): 10422–7. Bibcode:2004PNAS..10110422U. doi:10.1073/pnas.0402511101. PMC 478587. PMID 15240880. 
  8. ^ a b c d e f g h i Vigo, J. B., and J. T. Ellzey (2006). "Effects of Arsenic Toxicity at the Cellular Level: A Review". Texas Journal of Microscopy 37 (2): 45–49. 
  9. ^ a b Thompson DJ (September 1993). "A chemical hypothesis for arsenic methylation in mammals". Chemico-biological Interactions 88 (2-3): 89–14. doi:10.1016/0009-2797(93)90086-E. PMID 8403081. 
  10. ^ Vahter M, Concha G (July 2001). "Role of metabolism in arsenic toxicity". Pharmacology & Toxicology 89 (1): 1–5. doi:10.1034/j.1600-0773.2001.d01-128.x. PMID 11484904. 
  11. ^ Gebel TW (October 2002). "Arsenic methylation is a process of detoxification through accelerated excretion". International Journal of Hygiene and Environmental Health 205 (6): 505–8. doi:10.1078/1438-4639-00177. PMID 12455273. 
  12. ^ a b c Kitchin KT (May 2001). "Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites". Toxicology and Applied Pharmacology 172 (3): 249–61. doi:10.1006/taap.2001.9157. PMID 11312654. 
  13. ^ Kenyon EM, Fea M, Styblo M, Evans MV (2001). "Application of modelling techniques to the planning of in vitro arsenic kinetic studies". Alternatives to Laboratory Animals 29 (1): 15–33. PMID 11178572. 
  14. ^ Styblo M, Thomas DJ (April 2001). "Selenium modifies the metabolism and toxicity of arsenic in primary rat hepatocytes". Toxicology and Applied Pharmacology 172 (1): 52–61. doi:10.1006/taap.2001.9134. PMID 11264023. 
  15. ^ Aposhian HV, Maiorino RM, Dart RC, Perry DF (May 1989). "Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects". Clinical Pharmacology and Therapeutics 45 (5): 520–6. doi:10.1038/clpt.1989.67. PMID 2541962. 
  16. ^ Rodríguez VM, Del Razo LM, Limón-Pacheco JH, et al. (March 2005). "Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver". Toxicological Sciences 84 (1): 157–66. doi:10.1093/toxsci/kfi057. PMID 15601678. 
  17. ^ Rom, William N.; Markowitz, Steven B. (2007). Environmental and Occupational Medicine. Lippincott Williams & Wilkins. pp. 1014–5. ISBN 978-0-7817-6299-1. 
  18. ^ Hughes MF (July 2002). "Arsenic toxicity and potential mechanisms of action". Toxicology Letters 133 (1): 1–16. doi:10.1016/S0378-4274(02)00084-X. PMID 12076506. 
  19. ^ Gresser MJ (June 1981). "ADP-arsenate. Formation by submitochondrial particles under phosphorylating conditions". The Journal of Biological Chemistry 256 (12): 5981–3. PMID 7240187. 
  20. ^ Lee MY, Bae ON, Chung SM, Kang KT, Lee JY, Chung JH (March 2002). "Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease". Toxicology and Applied Pharmacology 179 (2): 83–8. doi:10.1006/taap.2001.9356. PMID 11884240. 
  21. ^ Harrisson JW, Packman EW, Abbott DD (February 1958). "Acute oral toxicity and chemical and physical properties of arsenic trioxides". A.M.A. Archives of Industrial Health 17 (2): 118–23. PMID 13497305. 
  22. ^ Hu Y, Su L, Snow ET (September 1998). "Arsenic toxicity is enzyme specific and its effects on ligation are not caused by the direct inhibition of DNA repair enzymes". Mutation Research 408 (3): 203–18. doi:10.1016/S0921-8777(98)00035-4. PMID 9806419. 
  23. ^ a b Gebel TW (March 2001). "Genotoxicity of arsenical compounds". International Journal of Hygiene and Environmental Health 203 (3): 249–62. doi:10.1078/S1438-4639(04)70036-X. PMID 11279822. 
  24. ^ Hartwig A, Schwerdtle T (February 2002). "Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications". Toxicology Letters 127 (1-3): 47–54. doi:10.1016/S0378-4274(01)00482-9. PMID 12052640. 
  25. ^ Yamanaka K, Hayashi H, Tachikawa M, et al. (November 1997). "Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics". Mutation Research 394 (1-3): 95–101. PMID 9434848. 
  26. ^ Bau DT, Wang TS, Chung CH, Wang AS, Wang AS, Jan KY (October 2002). "Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite". Environmental Health Perspectives 110 (Suppl 5): 753–6. PMC 1241239. PMID 12426126. 
  27. ^ Mass MJ, Tennant A, Roop BC, et al. (April 2001). "Methylated trivalent arsenic species are genotoxic". Chemical Research in Toxicology 14 (4): 355–61. doi:10.1021/tx000251l. PMID 11304123. 
  28. ^ Mäki-Paakkanen J, Kurttio P, Paldy A, Pekkanen J (1998). "Association between the clastogenic effect in peripheral lymphocytes and human exposure to arsenic through drinking water". Environmental and Molecular Mutagenesis 32 (4): 301–13. doi:10.1002/(SICI)1098-2280(1998)32:4<301::AID-EM3>3.0.CO;2-I. PMID 9882004. 
  29. ^ Warner ML, Moore LE, Smith MT, Kalman DA, Fanning E, Smith AH (1994). "Increased micronuclei in exfoliated bladder cells of individuals who chronically ingest arsenic-contaminated water in Nevada". Cancer Epidemiology, Biomarkers & Prevention 3 (7): 583–90. PMID 7827589. 
  30. ^ Gonsebatt ME, Vega L, Salazar AM, et al. (June 1997). "Cytogenetic effects in human exposure to arsenic". Mutation Research 386 (3): 219–28. doi:10.1016/S1383-5742(97)00009-4. PMID 9219560. 
  31. ^ a b c Bernstam L, Nriagu J (2000). "Molecular aspects of arsenic stress". Journal of Toxicology and Environmental Health. Part B, Critical Reviews 3 (4): 293–322. doi:10.1080/109374000436355. PMID 11055208. 
  32. ^ Yamanaka K, Hoshino M, Okamoto M, Sawamura R, Hasegawa A, Okada S (April 1990). "Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical". Biochemical and Biophysical Research Communications 168 (1): 58–64. doi:10.1016/0006-291X(90)91674-H. PMID 2158319. 
  33. ^ Ahmad R, Alam K, Ali R (February 2000). "Antigen binding characteristics of antibodies against hydroxyl radical modified thymidine monophosphate". Immunology Letters 71 (2): 111–5. doi:10.1016/S0165-2478(99)00177-7. PMID 10714438. 
  34. ^ Yamanaka K, Mizol M, Kato K, Hasegawa A, Nakano M, Okada S (May 2001). "Oral administration of dimethylarsinic acid, a main metabolite of inorganic arsenic, in mice promotes skin tumorigenesis initiated by dimethylbenz(a)anthracene with or without ultraviolet B as a promoter". Biological & Pharmaceutical Bulletin 24 (5): 510–4. doi:10.1248/bpb.24.510. PMID 11379771. 
  35. ^ Pi J, Yamauchi H, Kumagai Y, et al. (April 2002). "Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water". Environmental Health Perspectives 110 (4): 331–6. doi:10.1289/ehp.02110331. PMC 1240794. PMID 11940449. 
  36. ^ Wu MM, Chiou HY, Wang TW, et al. (October 2001). "Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan". Environmental Health Perspectives (Brogan &#38) 109 (10): 1011–7. doi:10.2307/3454955. JSTOR 3454955. PMC 1242077. PMID 11675266. 
  37. ^ Goering PL, Aposhian HV, Mass MJ, Cebrián M, Beck BD, Waalkes MP (May 1999). "The enigma of arsenic carcinogenesis: role of metabolism". Toxicological Sciences 49 (1): 5–14. doi:10.1093/toxsci/49.1.5. PMID 10367337. 
  38. ^ a b c Zhong CX, Mass MJ (July 2001). "Both hypomethylation and hypermethylation of DNA associated with arsenite exposure in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR". Toxicology Letters 122 (3): 223–34. doi:10.1016/S0378-4274(01)00365-4. PMID 11489357. 
  39. ^ Brambila EM, Achanzar WE, Qu W, Webber MM, Waalkes MP (September 2002). "Chronic arsenic-exposed human prostate epithelial cells exhibit stable arsenic tolerance: mechanistic implications of altered cellular glutathione and glutathione S-transferase". Toxicology and Applied Pharmacology 183 (2): 99–107. doi:10.1016/S0041-008X(02)99468-8. PMID 12387749. 
  40. ^ Vernhet L, Allain N, Bardiau C, Anger JP, Fardel O (January 2000). "Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals". Toxicology 142 (2): 127–34. doi:10.1016/S0300-483X(99)00148-1. PMID 10685512. 
  41. ^ Salerno M, Petroutsa M, Garnier-Suillerot A (April 2002). "The MRP1-mediated effluxes of arsenic and antimony do not require arsenic-glutathione and antimony-glutathione complex formation". Journal of Bioenergetics and Biomembranes 34 (2): 135–45. doi:10.1023/A:1015180026665. PMID 12018890. 
  42. ^ Gebel T (April 2000). "Confounding variables in the environmental toxicology of arsenic". Toxicology 144 (1-3): 155–62. doi:10.1016/S0300-483X(99)00202-4. PMID 10781883. 
  43. ^ a b Del Razo LM, Quintanilla-Vega B, Brambila-Colombres E, Calderón-Aranda ES, Manno M, Albores A (December 2001). "Stress proteins induced by arsenic". Toxicology and Applied Pharmacology 177 (2): 132–48. doi:10.1006/taap.2001.9291. PMID 11740912. 
  44. ^ Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M (November 1996). "The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase". The EMBO Journal 15 (22): 6269–79. PMC 452450. PMID 8947050. 
  45. ^ Ludwig S, Hoffmeyer A, Goebeler M, et al. (January 1998). "The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway". The Journal of Biological Chemistry 273 (4): 1917–22. doi:10.1074/jbc.273.4.1917. PMID 9442025. 
  46. ^ Simeonova PP, Luster MI (2000). "Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms?". Journal of Environmental Pathology, Toxicology and Oncology 19 (3): 281–6. PMID 10983894. 
  47. ^ Germolec DR, Yoshida T, Gaido K, et al. (November 1996). "Arsenic induces overexpression of growth factors in human keratinocytes". Toxicology and Applied Pharmacology 141 (1): 308–18. doi:10.1006/taap.1996.0288. PMID 8917704. 
  48. ^ Hamadeh HK, Vargas M, Lee E, Menzel DB (September 1999). "Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis". Biochemical and Biophysical Research Communications 263 (2): 446–9. doi:10.1006/bbrc.1999.1395. PMID 10491313. 
  49. ^ a b c d Hu Y, Jin X, Snow ET (July 2002). "Effect of arsenic on transcription factor AP-1 and NF-κB DNA binding activity and related gene expression". Toxicology Letters 133 (1): 33–45. doi:10.1016/S0378-4274(02)00083-8. PMID 12076508. 
  50. ^ a b Walton FS, Harmon AW, Paul DS, Drobná Z, Patel YM, Styblo M (August 2004). "Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes". Toxicology and Applied Pharmacology 198 (3): 424–33. doi:10.1016/j.taap.2003.10.026. PMID 15276423. 
  51. ^ a b Black PH (October 2003). "The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X". Brain, Behavior, and Immunity 17 (5): 350–64. doi:10.1016/S0889-1591(03)00048-5. PMID 12946657. 
  52. ^ Carey AL, Lamont B, Andrikopoulos S, Koukoulas I, Proietto J, Febbraio MA (March 2003). "Interleukin-6 gene expression is increased in insulin-resistant rat skeletal muscle following insulin stimulation". Biochemical and Biophysical Research Communications 302 (4): 837–40. doi:10.1016/S0006-291X(03)00267-5. PMID 12646246. 
  53. ^ Dandona P, Aljada A, Bandyopadhyay A (January 2004). "Inflammation: the link between insulin resistance, obesity and diabetes". Trends in Immunology 25 (1): 4–7. doi:10.1016/j.it.2003.10.013. PMID 14698276. 
  54. ^ Fischer CP, Perstrup LB, Berntsen A, Eskildsen P, Pedersen BK (November 2005). "Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans". Clinical Immunology 117 (2): 152–60. doi:10.1016/j.clim.2005.07.008. PMID 16112617. 
  55. ^ Gentry PR, Covington TR, Mann S, Shipp AM, Yager JW, Clewell HJ (January 2004). "Physiologically based pharmacokinetic modeling of arsenic in the mouse". Journal of Toxicology and Environmental Health. Part a 67 (1): 43–71. doi:10.1080/15287390490253660. PMID 14668111. 
  56. ^ a b Kota BP, Huang TH, Roufogalis BD (February 2005). "An overview on biological mechanisms of PPARs". Pharmacological Research 51 (2): 85–94. doi:10.1016/j.phrs.2004.07.012. PMID 15629253. 
  57. ^ Luquet, S., C. Gaudel, D. Holst, J. Lopez-Soriano, C. Jehl-Pietri, A. Fredenrich (2005). Biochimica et Biophysica Acta 1740: 313–317. 
  58. ^ a b Moraes LA, Piqueras L, Bishop-Bailey D (June 2006). "Peroxisome proliferator-activated receptors and inflammation". Pharmacology & Therapeutics 110 (3): 371–85. doi:10.1016/j.pharmthera.2005.08.007. PMID 16168490. 
  59. ^ Hara K, Okada T, Tobe K, et al. (April 2000). "The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes". Biochemical and Biophysical Research Communications 271 (1): 212–6. doi:10.1006/bbrc.2000.2605. PMID 10777704. 

External links and further reading[edit]