Editing Arsenic poisoning (section)

==Pathophysiology==
Arsenic interferes with cellular longevity by [[allosteric inhibition]] of an essential metabolic enzyme [[pyruvate dehydrogenase]] complex, which catalyzes the oxidation of [[pyruvate]] to [[acetyl-CoA]] by [[Nicotinamide adenine dinucleotide|NAD]]<sup>+</sup>. With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular [[apoptosis]]. Biochemically, arsenic prevents use of [[thiamine]] resulting in a clinical picture resembling [[thiamine deficiency]]. <ref>{{cite journal |last1=Singh |first1=Amrit |last2=Goel |first2=R. K. |last3=Kaur |first3=T. |title=Mechanisms Pertaining to Arsenic Toxicity |journal=Toxicology International |date=July 2011 |volume=18 |issue=2 |page=89 |doi=10.4103/0971-6580.84258 |doi-access=free |pmid=21976811 |pmc=3183630}}</ref> Poisoning with arsenic can raise lactate levels and lead to [[lactic acidosis]].<ref>{{cite journal |last1=Zhao |first1=Fei |last2=Severson |first2=Paul |last3=Pacheco |first3=Samantha |last4=Futscher |first4=Bernard |last5=Klimecki |first5=Walter |title=Arsenic Exposure Induces the Warburg Effect In Cultured Human Cells |journal=Toxicology and Applied Pharmacology |date=2013 |volume=271 |issue=1 |pages=72–77 |doi=10.1016/j.taap.2013.04.020 |pmid=23648393 |pmc=3714307|bibcode=2013ToxAP.271...72Z }}</ref> Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.{{citation needed|date=May 2013}}
Arsenic in cells clearly stimulates the production of [[hydrogen peroxide]] (H<sub>2</sub>O<sub>2</sub>). When the H<sub>2</sub>O<sub>2</sub> reacts with certain metals such as [[iron]] or [[manganese]] it produces a highly reactive [[hydroxyl radical]]. Inorganic [[arsenic trioxide]] found in ground water particularly affects [[voltage-gated potassium channel]]s,<ref>{{cite journal |vauthors=Zhou J, Wang W, Wei QF, Feng TM, Tan LJ, Yang BF |title=Effects of arsenic trioxide on voltage-dependent potassium channels and on cell proliferation of human multiple myeloma cells |journal=Chin. Med. J. |volume=120 |issue=14 |pages=1266–9 |date=July 2007 |pmid=17697580 |doi= 10.1097/00029330-200707020-00012|doi-access=free }}</ref>
disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, [[neutropenia]], [[high blood pressure]],<ref>{{cite journal | pages= 289–294 | issue= 3 | volume= 66 | journal= Pediatric Research | year= 2009 | pmid= 19542906 | title= Impaired Voltage Gated Potassium Channel Responses in a Fetal Lamb Model of Persistent Pulmonary Hypertension of the Newborn |doi= 10.1203/PDR.0b013e3181b1bc89 | vauthors=Konduri GG, Bakhutashvili I, Eis A, Gauthier KM | pmc= 3749926 }}</ref>
central nervous system dysfunction, [[anemia]], and death.

{{Blockquote|Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing [[fibrinolysis]]. Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-α, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis.|Pitchai Balakumar and Jagdeep Kaur, "Arsenic Exposure and Cardiovascular Disorders: An Overview", ''[[Cardiovascular Toxicology]]'', December 2009<ref>{{cite journal |last1=Balakumar |first1=Pitchai |last2=Kaur |first2=Jagdeep |date=December 2009 |title=Arsenic Exposure and Cardiovascular Disorders: An Overview |journal=Cardiovascular Toxicology |volume=9 |issue=4 |doi=10.1007/s12012-009-9050-6 |pmid=19787300 |pages=169–76 |s2cid=8063051 }}</ref>}}

Arsenic has also been shown to induce [[Ventricular hypertrophy|cardiac hypertrophy]] by activating certain [[transcription factor]]s involved in pathologically remodeling the heart.<ref>{{cite journal|last1=Kabir|first1=Raihan|last2=Sinha|first2=Prithvi|last3=Mishra|first3=Sumita|last4=Ebenebe|first4=Obialunanma V.|last5=Taube|first5=Nicole|last6=Oeing|first6=Chistian U.|last7=Keceli|first7=Gizem|last8=Chen|first8=Rui|last9=Paolocci|first9=Nazareno|last10=Rule|first10=Ana|last11=Kohr|first11=Mark J.|date=2021-04-01|title=Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart|journal=American Journal of Physiology. Heart and Circulatory Physiology|volume=320|issue=4|pages=H1321–H1336|doi=10.1152/ajpheart.00435.2020|issn=1522-1539|pmc=8260381|pmid=33481702}}</ref> Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt [[adenosine triphosphate|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 [[nicotinamide adenine dinucleotide|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]], 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.<ref>{{cite book | pages = 512 | publisher = McGraw-Hill | isbn =  978-0-07-138914-3 | title = Casarett and Doull's Essentials of Toxicology | year = 2003|  first = Curtis | last = Klaassen  | author2 = Watkins, John}}</ref>

===Mechanism===
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.<ref name=Hughes2002>{{cite journal|author=Hughes MF |title=Arsenic toxicity and potential mechanisms of action |journal=[[Toxicology Letters]] |volume=133 |issue=1 |pages=1–16 |date=July 2002 |pmid=12076506 |doi=10.1016/S0378-4274(02)00084-X|url=https://zenodo.org/record/1260065 }}</ref> (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the [[glyceraldehyde 3-phosphate 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.<ref>{{cite journal|author=Gresser MJ |title=ADP-arsenate. Formation by submitochondrial particles under phosphorylating conditions |journal=The Journal of Biological Chemistry |volume=256 |issue=12 |pages=5981–3 |date=June 1981 |doi=10.1016/S0021-9258(19)69115-5 |pmid=7240187 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7240187|doi-access=free }}</ref> 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.<ref>{{cite journal|vauthors=Lee MY, Bae ON, Chung SM, Kang KT, Lee JY, Chung JH |title=Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease |journal=Toxicology and Applied Pharmacology |volume=179 |issue=2 |pages=83–8 |date=March 2002 |pmid=11884240 |doi=10.1006/taap.2001.9356|bibcode=2002ToxAP.179...83L }}</ref> 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.<ref>{{cite journal|vauthors=Harrisson JW, Packman EW, Abbott DD |title=Acute oral toxicity and chemical and physical properties of arsenic trioxides |journal=AMA Archives of Industrial Health |volume=17 |issue=2 |pages=118–23 |date=February 1958 |pmid=13497305}}</ref>

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures.<ref>{{cite journal|vauthors=Hartwig A, Schwerdtle T |title=Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications |journal=Toxicology Letters |volume=127 |issue=1–3 |pages=47–54 |date=February 2002 |pmid=12052640 |doi=10.1016/S0378-4274(01)00482-9}}</ref> Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial {{nowrap|type II}} cells.<ref name=Yamanaka1997>{{cite journal|vauthors=Yamanaka K, Hayashi H, Tachikawa M |title=Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics |journal=Mutation Research |volume=394 |issue=1–3 |pages=95–101 |date=November 1997 |pmid=9434848 |doi=10.1016/s1383-5718(97)00130-7|bibcode=1997MRGTE.394...95Y |display-authors=etal}}</ref><ref name=Bau2002>{{cite journal|vauthors=Bau DT, Wang TS, Chung CH, Wang AS, Wang AS, Jan KY |title=Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite |journal=Environmental Health Perspectives |volume=110  |issue=Suppl 5 |pages=753–6 |date=October 2002 |pmid=12426126 |pmc=1241239 |doi=10.1289/ehp.02110s5753|bibcode=2002EnvHP.110S.753B }}</ref>

MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA.<ref name=Mass2001>{{cite journal|vauthors=Mass MJ, Tennant A, Roop BC |title=Methylated trivalent arsenic species are genotoxic |journal=[[Chemical Research in Toxicology]] |volume=14 |issue=4 |pages=355–61 |date=April 2001 |pmid=11304123 |doi=10.1021/tx000251l|display-authors=etal}}</ref> Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations,<ref name="Maki-Paakkanen1998">{{cite journal|vauthors=Mäki-Paakkanen J, Kurttio P, Paldy A, Pekkanen J |title=Association between the clastogenic effect in peripheral lymphocytes and human exposure to arsenic through drinking water |journal=Environmental and Molecular Mutagenesis |volume=32 |issue=4 |pages=301–13 |year=1998 |pmid=9882004 |doi=10.1002/(SICI)1098-2280(1998)32:4<301::AID-EM3>3.0.CO;2-I|bibcode=1998EnvMM..32..301M |s2cid=25681878 }}</ref> micronuclei<ref name=Warner1994>{{cite journal|vauthors=Warner ML, Moore LE, Smith MT, Kalman DA, Fanning E, Smith AH |title=Increased micronuclei in exfoliated bladder cells of individuals who chronically ingest arsenic-contaminated water in Nevada |journal=Cancer Epidemiology, Biomarkers & Prevention |volume=3 |issue=7 |pages=583–90 |year=1994 |pmid=7827589 |url=http://cebp.aacrjournals.org/cgi/pmidlookup?view=long&pmid=7827589}}</ref><ref name=Gonsebatt1997>{{cite journal|vauthors=Gonsebatt ME, Vega L, Salazar AM |title=Cytogenetic effects in human exposure to arsenic |journal=Mutation Research |volume=386 |issue=3 |pages=219–28 |date=June 1997 |pmid=9219560 |doi=10.1016/S1383-5742(97)00009-4|bibcode=1997MRRMR.386..219G |display-authors=etal}}</ref> 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.<ref name=Bernstam2000>{{cite journal|vauthors=Bernstam L, Nriagu J |title=Molecular aspects of arsenic stress |journal=Journal of Toxicology and Environmental Health, Part B|volume=3 |issue=4 |pages=293–322 |year=2000 |pmid=11055208 |doi=10.1080/109374000436355|bibcode=2000JTEHB...3..293N |s2cid=42312354 }}</ref>

DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.<ref name=Yamanaka1990>{{cite journal|vauthors=Yamanaka K, Hoshino M, Okamoto M, Sawamura R, Hasegawa A, Okada S |title=Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical |journal=Biochemical and Biophysical Research Communications |volume=168 |issue=1 |pages=58–64 |date=April 1990 |pmid=2158319 |doi=10.1016/0006-291X(90)91674-H}}</ref>
Both DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, formation of reactive oxygen species can be promoted.<ref name=Ahmad2000>{{cite journal|vauthors=Ahmad R, Alam K, Ali R |title=Antigen binding characteristics of antibodies against hydroxyl radical modified thymidine monophosphate |journal=Immunology Letters |volume=71 |issue=2 |pages=111–5 |date=February 2000 |pmid=10714438 |doi=10.1016/S0165-2478(99)00177-7}}</ref>
Moreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially the ones containing thiol groups. The accumulation of reactive oxygen species like that 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'-deoxyguanosine (as a biomarker of DNA damage byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased.<ref name=Yamanaka2001>{{cite journal|vauthors=Yamanaka K, Mizol M, Kato K, Hasegawa A, Nakano M, Okada S |title=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 |journal=Biological & Pharmaceutical Bulletin |volume=24 |issue=5 |pages=510–4 |date=May 2001 |pmid=11379771 |doi=10.1248/bpb.24.510|doi-access=free }}</ref> This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides 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.<ref name=Pi2002>{{cite journal|doi=10.1289/ehp.02110331 |vauthors=Pi J, Yamauchi H, Kumagai Y |title=Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water |journal=Environmental Health Perspectives |volume=110 |issue=4 |pages=331–6 |date=April 2002 |pmid=11940449 |pmc=1240794|bibcode=2002EnvHP.110..331P |display-authors=etal}}</ref>

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.<ref name=Wu2001>{{cite journal|vauthors=Wu MM, Chiou HY, Wang TW |title=Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan |journal=Environmental Health Perspectives |volume=109 |issue=10 |pages=1011–7 |date=October 2001 |pmid=11675266 |pmc=1242077 |doi=10.2307/3454955 |jstor=3454955|display-authors=etal}}</ref> 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.<ref name=Kitchin2001/> Considering that a high partial pressure of oxygen is present in lungs and DMA(III) 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 later 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.<ref name=Goering1999>{{cite journal|vauthors=Goering PL, Aposhian HV, Mass MJ, Cebrián M, Beck BD, Waalkes MP |title=The enigma of arsenic carcinogenesis: role of metabolism |journal=Toxicological Sciences |volume=49 |issue=1 |pages=5–14 |date=May 1999 |pmid=10367337 |doi=10.1093/toxsci/49.1.5|doi-access=free }}</ref> 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 polymerase chain reactions.<ref name=Zhong2001>{{cite journal|vauthors=Zhong CX, Mass MJ |title=Both hypomethylation and hypermethylation of DNA associated with arsenite exposure in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR |journal=Toxicology Letters |volume=122 |issue=3 |pages=223–34 |date=July 2001 |pmid=11489357 |doi=10.1016/S0378-4274(01)00365-4|url=https://zenodo.org/record/1260063 }}</ref> It turned out that six of the fragments were hyper- and two of them were hypomethylated.<ref name=Zhong2001/> Higher levels of DNA methyltransferase mRNA and enzyme activity were found.<ref name=Zhong2001/>

Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to [[carcinogenesis]].<ref name=Kitchin2001/> From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity.<ref name=Gebel2001>{{cite journal|author=Gebel TW |title=Genotoxicity of arsenical compounds |journal=International Journal of Hygiene and Environmental Health |volume=203 |issue=3 |pages=249–62 |date=March 2001 |pmid=11279822 |doi=10.1078/S1438-4639(04)70036-X|bibcode=2001IJHEH.203..249G }}</ref><ref name=Brambila2002>{{cite journal|vauthors=Brambila EM, Achanzar WE, Qu W, Webber MM, Waalkes MP |title=Chronic arsenic-exposed human prostate epithelial cells exhibit stable arsenic tolerance: mechanistic implications of altered cellular glutathione and glutathione S-transferase |journal=Toxicology and Applied Pharmacology |volume=183 |issue=2 |pages=99–107 |date=September 2002 |pmid=12387749 |doi=10.1016/S0041-008X(02)99468-8}}</ref> MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux.<ref name=Vernhet2000>{{cite journal|vauthors=Vernhet L, Allain N, Bardiau C, Anger JP, Fardel O |title=Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals |journal=Toxicology |volume=142 |issue=2 |pages=127–34 |date=January 2000 |pmid=10685512 |doi=10.1016/S0300-483X(99)00148-1}}</ref> The efflux requires glutathione, but no arsenic-glutathione complex formation.<ref name=Salerno2002>{{cite journal|vauthors=Salerno M, Petroutsa M, Garnier-Suillerot A |title=The MRP1-mediated effluxes of arsenic and antimony do not require arsenic-glutathione and antimony-glutathione complex formation |journal=Journal of Bioenergetics and Biomembranes |volume=34 |issue=2 |pages=135–45 |date=April 2002 |pmid=12018890 |doi=10.1023/A:1015180026665|s2cid=588472 }}</ref>

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.<ref name=Gebel2000>{{cite journal|author=Gebel T |title=Confounding variables in the environmental toxicology of arsenic |journal=Toxicology |volume=144 |issue=1–3 |pages=155–62 |date=April 2000 |pmid=10781883 |doi=10.1016/S0300-483X(99)00202-4|bibcode=2000Toxgy.144..155G }}</ref>

===Kinetics===
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.<ref name="Ueki">{{cite journal|vauthors=Ueki K, Kondo T, Tseng YH, Kahn CR |title=Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse |journal=[[Proceedings of the National Academy of Sciences of the United States of America]] |volume=101 |issue=28 |pages=10422–7 |date=July 2004 |pmid=15240880 |pmc=478587 |doi=10.1073/pnas.0402511101|bibcode = 2004PNAS..10110422U |doi-access=free }}</ref> 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).<ref name="Vigo"/> Dimethylarsenic acid is also known as [[Agent Blue]] and was used as herbicide in the American war in [[Vietnam]].

In humans inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione 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.<ref name="thom">{{cite journal|author=Thompson DJ |title=A chemical hypothesis for arsenic methylation in mammals |journal=[[Chemico-Biological Interactions]] |volume=88 |issue=2–3 |pages=89–114 |date=September 1993 |pmid=8403081 |doi=10.1016/0009-2797(93)90086-E|bibcode=1993CBI....88...89T }}</ref> Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).

Methylation had been regarded as a detoxification process, {{by whom|date=December 2013}} but reduction from +5 As to +3 As may be considered as a bioactivation {{clarify|date=December 2013}} instead.<ref name="vaht">{{cite journal|vauthors=Vahter M, Concha G |title=Role of metabolism in arsenic toxicity |journal=[[Pharmacology & Toxicology]] |volume=89 |issue=1 |pages=1–5 |date=July 2001 |pmid=11484904 |doi=10.1034/j.1600-0773.2001.d01-128.x|doi-broken-date=21 December 2024 }}</ref> 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 group]]s than inorganic pentavalent arsenics.<ref name="thom"/> Gebel (2002) stated that methylation is a detoxification through accelerated excretion.<ref name=Gebel2002>{{cite journal|author=Gebel TW |title=Arsenic methylation is a process of detoxification through accelerated excretion |journal=International Journal of Hygiene and Environmental Health |volume=205 |issue=6 |pages=505–8 |date=October 2002 |pmid=12455273 |doi=10.1078/1438-4639-00177|bibcode=2002IJHEH.205..505G }}</ref> With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.<ref name=Kitchin2001>{{cite journal|author=Kitchin KT |title=Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites |journal=[[Toxicology and Applied Pharmacology]] |volume=172 |issue=3 |pages=249–61 |date=May 2001 |pmid=11312654 |doi=10.1006/taap.2001.9157|bibcode=2001ToxAP.172..249K |url=https://zenodo.org/record/1229982 }}</ref><ref name=Kenyon2001>{{cite journal|vauthors=Kenyon EM, Fea M, Styblo M, Evans MV |title=Application of modelling techniques to the planning of in vitro arsenic kinetic studies |journal=Alternatives to Laboratory Animals |volume=29 |issue=1 |pages=15–33 |year=2001 |pmid=11178572|doi=10.1177/026119290102900109 |s2cid=594362 |doi-access=free }}</ref><ref name=Styblo2002>{{cite journal|vauthors=Styblo M, Thomas DJ |title=Selenium modifies the metabolism and toxicity of arsenic in primary rat hepatocytes |journal=Toxicology and Applied Pharmacology |volume=172 |issue=1 |pages=52–61 |date=April 2001 |pmid=11264023 |doi=10.1006/taap.2001.9134|bibcode=2001ToxAP.172...52S }}</ref>

Arsenic, especially +3 As, binds to single, but with higher affinity to [[vicinal (chemistry)|vicinal]] [[sulfhydryl group]]s, thus reacts with a variety of [[protein]]s and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification.<ref name=Aposhian1989>{{cite journal|doi=10.1038/clpt.1989.67 |vauthors=Aposhian HV, Maiorino RM, Dart RC, Perry DF |title=Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects |journal=Clinical Pharmacology and Therapeutics |volume=45 |issue=5 |pages=520–6 |date=May 1989 |pmid=2541962|s2cid=25174222 }}</ref> Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase<ref name=Rodriguez2005>{{cite journal|vauthors=Rodríguez VM, Del Razo LM, Limón-Pacheco JH |title=Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver |journal=[[Toxicological Sciences]] |volume=84 |issue=1 |pages=157–66 |date=March 2005 |pmid=15601678 |doi=10.1093/toxsci/kfi057|display-authors=etal|doi-access=free }}</ref> and thioredoxin reductase.<ref name="willi">{{cite book |first1=William N. |last1=Rom |first2=Steven B. |last2=Markowitz |title=Environmental and Occupational Medicine |publisher=Lippincott Williams & Wilkins |year=2007 |pages=1014–5 |url=https://books.google.com/books?id=H4Sv9XY296oC&pg=RA2-PA1014 |isbn=978-0-7817-6299-1 |url-status=live |archive-url=https://web.archive.org/web/20170910145312/https://books.google.com/books?id=H4Sv9XY296oC&pg=RA2-PA1014&lpg=RA2-PA1014#PRA2-PA1014,M1 |archive-date=2017-09-10 }}</ref>

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers.<ref name="Vigo">{{cite journal|author1=Vigo, J. B. |author2=J. T. Ellzey  | title = Effects of Arsenic Toxicity at the Cellular Level: A Review | journal = Texas Journal of Microscopy | volume = 37 | issue = 2 | year = 2006 | pages = 45–49}}</ref> 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.<ref name="Vigo"/>

The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200&nbsp;mg or 1&nbsp;mg/kg/day.<ref name="dart">{{cite Q|Q126687121|pp=1393–1401}}</ref>

===Heat shock response===
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, and 110 kDa as well as [[metallothionein]], [[ubiquitin]], mitogen-activated [MAP] kinases, [[Extracellular signal-regulated kinases|extracellular regulated kinase]] [ERK], c-jun terminal kinases [JNK] and p38.<ref name=Bernstam2000/><ref name=DelRazo2001>{{cite journal|vauthors=Del Razo LM, Quintanilla-Vega B, Brambila-Colombres E, Calderón-Aranda ES, Manno M, Albores A |title=Stress proteins induced by arsenic |journal=Toxicology and Applied Pharmacology |volume=177 |issue=2 |pages=132–48 |date=December 2001 |pmid=11740912 |doi=10.1006/taap.2001.9291|bibcode=2001ToxAP.177..132D }}</ref>
Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines.<ref name=Bernstam2000/><ref name=Cavigelli1996>{{cite journal|vauthors=Cavigelli M, Li WW, Lin A, Su B, Yoshioka K, Karin M |title=The tumor promoter arsenite stimulates AP-1 activity by inhibiting a JNK phosphatase |journal=The EMBO Journal |volume=15 |issue=22 |pages=6269–79 |date=November 1996 |pmid=8947050 |pmc=452450|doi=10.1002/j.1460-2075.1996.tb01017.x }}</ref><ref name=Ludwig1998>{{cite journal|vauthors=Ludwig S, Hoffmeyer A, Goebeler M |title=The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway |journal=The Journal of Biological Chemistry |volume=273 |issue=4 |pages=1917–22 |date=January 1998 |pmid=9442025 |doi=10.1074/jbc.273.4.1917|display-authors=etal|doi-access=free }}</ref> The effects are largely dependent on the dosing regime and may be as well inversed.

As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species 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.<ref name=DelRazo2001/><ref name=Simeonova2000>{{cite journal|vauthors=Simeonova PP, Luster MI |title=Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms? |journal=Journal of Environmental Pathology, Toxicology and Oncology |volume=19 |issue=3 |pages=281–6 |year=2000 |pmid=10983894}}</ref> Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.<ref>{{cite journal|vauthors=Germolec DR, Yoshida T, Gaido K |title=Arsenic induces overexpression of growth factors in human keratinocytes |journal=Toxicology and Applied Pharmacology |volume=141 |issue=1 |pages=308–18 |date=November 1996 |pmid=8917704 |doi=10.1006/taap.1996.0288|display-authors=etal}}</ref>

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.<ref name=Hamadeh1999>{{cite journal|vauthors=Hamadeh HK, Vargas M, Lee E, Menzel DB |title=Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis |journal=Biochemical and Biophysical Research Communications |volume=263 |issue=2 |pages=446–9 |date=September 1999 |pmid=10491313 |doi=10.1006/bbrc.1999.1395}}</ref> 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.<ref name=hu2002/> The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis.<ref name=hu2002/> 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|date=November 2009}}

===Oxidative stress===
Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, AP-1, and NF-κB,<ref name = Vigo/><ref name=hu2002>{{cite journal|vauthors=Hu Y, Jin X, Snow ET |title=Effect of arsenic on transcription factor AP-1 and NF-κB DNA binding activity and related gene expression |journal=Toxicology Letters |volume=133 |issue=1 |pages=33–45 |date=July 2002 |pmid=12076508 |doi=10.1016/S0378-4274(02)00083-8|url=https://figshare.com/articles/journal_contribution/22858700 }}</ref><ref name = walton>{{cite journal|vauthors=Walton FS, Harmon AW, Paul DS, Drobná Z, Patel YM, Styblo M |title=Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes |journal=Toxicology and Applied Pharmacology |volume=198 |issue=3 |pages=424–33 |date=August 2004 |pmid=15276423 |doi=10.1016/j.taap.2003.10.026|bibcode=2004ToxAP.198..424W }}</ref> as well as the pro-inflammatory cytokines IL-8 and TNF-α.<ref name="Vigo"/><ref name=hu2002/><ref name = walton/><ref name = black>{{cite journal|author=Black PH |title=The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type&nbsp;II diabetes and metabolic syndrome X |journal=Brain, Behavior, and Immunity |volume=17 |issue=5 |pages=350–64 |date=October 2003 |pmid=12946657 |doi=10.1016/S0889-1591(03)00048-5|s2cid=39222261 }}</ref><ref>{{cite journal|vauthors=Carey AL, Lamont B, Andrikopoulos S, Koukoulas I, Proietto J, Febbraio MA |title=Interleukin-6 gene expression is increased in insulin-resistant rat skeletal muscle following insulin stimulation |journal=Biochemical and Biophysical Research Communications |volume=302 |issue=4 |pages=837–40 |date=March 2003 |pmid=12646246 |doi=10.1016/S0006-291X(03)00267-5}}</ref><ref>{{cite journal|vauthors=Dandona P, Aljada A, Bandyopadhyay A |title=Inflammation: the link between insulin resistance, obesity and diabetes |journal=Trends in Immunology |volume=25 |issue=1 |pages=4–7 |date=January 2004 |pmid=14698276 |doi=10.1016/j.it.2003.10.013}}</ref><ref>{{cite journal|vauthors=Fischer CP, Perstrup LB, Berntsen A, Eskildsen P, Pedersen BK |title=Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans |journal=Clinical Immunology |volume=117 |issue=2 |pages=152–60 |date=November 2005 |pmid=16112617 |doi=10.1016/j.clim.2005.07.008}}</ref><ref>{{cite journal|vauthors=Gentry PR, Covington TR, Mann S, Shipp AM, Yager JW, Clewell HJ |title=Physiologically based pharmacokinetic modeling of arsenic in the mouse |journal=Journal of Toxicology and Environmental Health, Part A |volume=67 |issue=1 |pages=43–71 |date=January 2004 |pmid=14668111 |doi=10.1080/15287390490253660|bibcode=2004JTEHA..67...43G |s2cid=12481907 }}</ref> <!-- Table 1 (which will be posted later because it is still under construction) summarizes a number of rodent hepatic genes with differential expression associated with arsenic. These genes have been grouped according to functions such as oxidative stress, signal transduction, inflammation, and growth factor/hormone receptors.<ref>{{cite journal |vauthors=Chen H, Liu J, Merrick BA, Waalkes MP |title=Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology |journal=Molecular Carcinogenesis |volume=30 |issue=2 |pages=79–87 |date=February 2001 |pmid=11241755 |doi=10.1002/1098-2744(200102)30:2<79::AID-MC1016>3.0.CO;2-F}}</ref> --> 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.<ref name = kota>{{cite journal|vauthors=Kota BP, Huang TH, Roufogalis BD |title=An overview on biological mechanisms of PPARs |journal=Pharmacological Research |volume=51 |issue=2 |pages=85–94 |date=February 2005 |pmid=15629253 |doi=10.1016/j.phrs.2004.07.012}}</ref><ref>{{cite journal|last1=Luquet|first1=Serge|last2=Gaudel|first2=Celine|last3=Holst|first3=Dorte|last4=Lopez-Soriano|first4=Joaquin|last5=Jehl-Pietri|first5=Chantal|last6=Fredenrich|first6=Alexandre|last7=Grimaldi|first7=Paul A.|title=Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|date=May 2005|volume=1740|issue=2|pages=313–317|doi=10.1016/j.bbadis.2004.11.011|pmid=15949697|doi-access=free}}</ref><ref name = moraes>{{cite journal|vauthors=Moraes LA, Piqueras L, Bishop-Bailey D |title=Peroxisome proliferator-activated receptors and inflammation |journal=Pharmacology & Therapeutics |volume=110 |issue=3 |pages=371–85 |date=June 2006 |pmid=16168490 |doi=10.1016/j.pharmthera.2005.08.007}}</ref> Recent scientific evidence has elucidated the physiological roles of the PPARs 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.<ref name = Vigo/><ref name= black/><ref name = kota/><ref name = moraes/><ref>{{cite journal|vauthors=Hara K, Okada T, Tobe K |title=The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes |journal=Biochemical and Biophysical Research Communications |volume=271 |issue=1 |pages=212–6 |date=April 2000 |pmid=10777704 |doi=10.1006/bbrc.2000.2605|display-authors=etal}}</ref>

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