Editing Arsenic poisoning (section)

===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>