Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects
The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arse...
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description | The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAs
III
) and dimethylarsinous acid (DMAs
III
), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAs
III
and DMAs
III
in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAs
III
and DMAs
III
in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAs
III
and DMAs
III
formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed. |
doi_str_mv | 10.1007/s00204-021-03028-w |
format | Article |
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III
) and dimethylarsinous acid (DMAs
III
), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAs
III
and DMAs
III
in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAs
III
and DMAs
III
in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAs
III
and DMAs
III
formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.</description><identifier>ISSN: 0340-5761</identifier><identifier>ISSN: 1432-0738</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-021-03028-w</identifier><identifier>PMID: 33768354</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Analytical methods ; Arsenic ; Arsenic - toxicity ; Arsenicals ; Biocompatibility ; Biological properties ; Biological samples ; Biomedical and Life Sciences ; Biomedicine ; Cacodylic Acid - analogs & derivatives ; Cells, Cultured ; Chronic exposure ; Detoxification ; Environmental Health ; Health risks ; Humans ; Metabolism ; Metabolites ; Methylation ; Methyltransferase ; Methyltransferases ; Occupational Medicine/Industrial Medicine ; Oxidation ; Oxidation-Reduction ; Pathogenesis ; Pharmacology/Toxicology ; Quantitation ; Review Article ; Valence</subject><ispartof>Archives of toxicology, 2021-05, Vol.95 (5), p.1547-1572</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-f4e58332dd93baea0c01979edbbd0a760596ad1022ff58a136df020de414b0283</citedby><cites>FETCH-LOGICAL-c540t-f4e58332dd93baea0c01979edbbd0a760596ad1022ff58a136df020de414b0283</cites><orcidid>0000-0001-6764-1900</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00204-021-03028-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00204-021-03028-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33768354$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Stýblo, Miroslav</creatorcontrib><creatorcontrib>Venkatratnam, Abhishek</creatorcontrib><creatorcontrib>Fry, Rebecca C.</creatorcontrib><creatorcontrib>Thomas, David J.</creatorcontrib><title>Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><addtitle>Arch Toxicol</addtitle><description>The toxic metalloid inorganic arsenic (iAs) is widely distributed in the environment. Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAs
III
) and dimethylarsinous acid (DMAs
III
), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAs
III
and DMAs
III
in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAs
III
and DMAs
III
in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAs
III
and DMAs
III
formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.</description><subject>Analytical methods</subject><subject>Arsenic</subject><subject>Arsenic - toxicity</subject><subject>Arsenicals</subject><subject>Biocompatibility</subject><subject>Biological properties</subject><subject>Biological samples</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cacodylic Acid - analogs & derivatives</subject><subject>Cells, Cultured</subject><subject>Chronic exposure</subject><subject>Detoxification</subject><subject>Environmental Health</subject><subject>Health risks</subject><subject>Humans</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Methylation</subject><subject>Methyltransferase</subject><subject>Methyltransferases</subject><subject>Occupational Medicine/Industrial Medicine</subject><subject>Oxidation</subject><subject>Oxidation-Reduction</subject><subject>Pathogenesis</subject><subject>Pharmacology/Toxicology</subject><subject>Quantitation</subject><subject>Review Article</subject><subject>Valence</subject><issn>0340-5761</issn><issn>1432-0738</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kU1v1DAQhi0EokvhD3BAkbj00NCxHScOByRU8SVV6gXOlhNPUpesvdjeVv33ne6W8nGofBjZ88zrmXkZe83hHQfoTjKAgKYGwWuQIHR9_YSteCNFDZ3UT9kKZAO16lp-wF7kfAnAhe7lc3YgZddqqZoV-3me_OxDPq4mW_C4ssFVdiw-hlzFqVpjubhZKOOqkvyVXTCUu0c7xMUX3DE-xDTb4MfKpowU31ebFOeEOe_k6JI3OJb8kj2b7JLx1X08ZD8-f_p--rU-O__y7fTjWT2qBko9Nai0lMK5Xg4WLYzA-65HNwwObNeC6lvrOAgxTUpbLls30SIcNrwZaA3ykH3Y6262wxrdSD0nu5hN8mubbky03vybCf7CzPHK6E5orYEEju4FUvy1xVzM2ucRl8UGjNtshIJWdFppRejb_9DLuE2BxiOKDs3RtkSJPTXSLnLC6aEZDubOS7P30pCXZueluaaiN3-P8VDy2zwC5B7IlAozpj9_PyJ7C-x7rJI</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Stýblo, Miroslav</creator><creator>Venkatratnam, Abhishek</creator><creator>Fry, Rebecca C.</creator><creator>Thomas, David J.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T2</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>MBDVC</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6764-1900</orcidid></search><sort><creationdate>20210501</creationdate><title>Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects</title><author>Stýblo, Miroslav ; 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Chronic exposure to iAs from environmental sources has been linked to a variety of human diseases. Methylation of iAs is the primary pathway for metabolism of iAs. In humans, methylation of iAs is catalyzed by arsenic (+ 3 oxidation state) methyltransferase (AS3MT). Conversion of iAs to mono- and di-methylated species (MAs and DMAs) detoxifies iAs by increasing the rate of whole body clearance of arsenic. Interindividual differences in iAs metabolism play key roles in pathogenesis of and susceptibility to a range of disease outcomes associated with iAs exposure. These adverse health effects are in part associated with the production of methylated trivalent arsenic species, methylarsonous acid (MAs
III
) and dimethylarsinous acid (DMAs
III
), during AS3MT-catalyzed methylation of iAs. The formation of these metabolites activates iAs to unique forms that cause disease initiation and progression. Taken together, the current evidence suggests that methylation of iAs is a pathway for detoxification and for activation of the metalloid. Beyond this general understanding of the consequences of iAs methylation, many questions remain unanswered. Our knowledge of metabolic targets for MAs
III
and DMAs
III
in human cells and mechanisms for interactions between these arsenicals and targets is incomplete. Development of novel analytical methods for quantitation of MAs
III
and DMAs
III
in biological samples promises to address some of these gaps. Here, we summarize current knowledge of the enzymatic basis of MAs
III
and DMAs
III
formation, the toxic actions of these metabolites, and methods available for their detection and quantification in biomatrices. Major knowledge gaps and future research directions are also discussed.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>33768354</pmid><doi>10.1007/s00204-021-03028-w</doi><tpages>26</tpages><orcidid>https://orcid.org/0000-0001-6764-1900</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Analytical methods Arsenic Arsenic - toxicity Arsenicals Biocompatibility Biological properties Biological samples Biomedical and Life Sciences Biomedicine Cacodylic Acid - analogs & derivatives Cells, Cultured Chronic exposure Detoxification Environmental Health Health risks Humans Metabolism Metabolites Methylation Methyltransferase Methyltransferases Occupational Medicine/Industrial Medicine Oxidation Oxidation-Reduction Pathogenesis Pharmacology/Toxicology Quantitation Review Article Valence |
title | Origins, fate, and actions of methylated trivalent metabolites of inorganic arsenic: progress and prospects |
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