{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T04:39:38Z","timestamp":1762144778063},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. A semi-mechanistic cellular-level toxicokinetic (TK) model was developed in order to describe the uptake, biotransformation and clearance of arsenical species in human hepatocytes. Notable features of this model are the incorporation of arsenic-glutathione complex formation and a \"switch-like\" formulation to describe the antioxidant response of hepatocytes to arsenic exposure.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The cellular-level TK model applies mass action kinetics in order to predict the concentrations of trivalent and pentavalent arsenicals in hepatocytes. The model simulates uptake of arsenite (iAs<jats:sup>III<\/jats:sup>) via aquaporin isozymes 9 (AQP9s), glutathione (GSH) conjugation, methylation by arsenic methyltransferase (AS3MT), efflux through multidrug resistant proteins (MRPs) and the induced antioxidant response via thioredoxin reductase (TR) activity. The model was parameterized by optimization of model estimates for arsenite (iAs<jats:sup>III<\/jats:sup>), monomethylated (MMA) and dimethylated (DMA) arsenicals concentrations with time-course experimental data in human hepatocytes for a time span of 48 hours, and dose-response data at 24 hours for a range of arsenite concentrations from 0.1 to 10 \u03bcM. Global sensitivity analysis of the model showed that at low doses the transport parameters had a dominant role, whereas at higher doses the biotransformation parameters were the most significant. A parametric comparison of the TK model with an analogous model developed for rat hepatocytes from the literature demonstrated that the biotransformation of arsenite (e.g. GSH conjugation) has a large role in explaining the variation in methylation between rats and humans.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The cellular-level TK model captures the temporal modes of arsenical accumulation in human hepatocytes. It highlighted the key biological processes that influence arsenic metabolism by explicitly modelling the metabolic network of GSH-adducts formation. The parametric comparison with the TK model developed for rats suggests that the variability in GSH conjugation could have an important role in inter-species variability of arsenical methylation. The TK model can be incorporated into larger-scale physiologically based toxicokinetic (PBTK) models of arsenic for improving the estimates of PBTK model parameters.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-5-16","type":"journal-article","created":{"date-parts":[[2011,2,17]],"date-time":"2011-02-17T19:17:13Z","timestamp":1297970233000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes - Incorporation of cellular antioxidant response and threshold-dependent behavior"],"prefix":"10.1186","volume":"5","author":[{"given":"Spyros K","family":"Stamatelos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J","family":"Brinkerhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sastry S","family":"Isukapalli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panos G","family":"Georgopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2011,1,25]]},"reference":[{"key":"605_CR1","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1021\/cr00094a002","volume":"89","author":"WR Cullen","year":"1989","unstructured":"Cullen WR, Reimer KJ: Arsenic Speciation in the Environment. Chemical Reviews. 1989, 89: 713-764. 10.1021\/cr00094a002.","journal-title":"Chemical Reviews"},{"key":"605_CR2","volume-title":"Atlanta: Agency for Toxic Substances and Disease Registry, US Department of Health and Human Services","author":"ATSDR","year":"2007","unstructured":"ATSDR: Toxicological Profile for Arsenic. Atlanta: Agency for Toxic Substances and Disease Registry, US Department of Health and Human Services. 2007,"},{"key":"605_CR3","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1080\/10408440802291505","volume":"39","author":"U Schuhmacher-Wolz","year":"2009","unstructured":"Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K: Oral exposure to inorganic arsenic: evaluation of its carcinogenic and non-carcinogenic effects. Critical Reviews in Toxicology. 2009, 39: 271-298. 10.1080\/10408440802291505","journal-title":"Critical Reviews in Toxicology"},{"key":"605_CR4","first-page":"436","volume":"128","author":"DN Guha Mazumder","year":"2008","unstructured":"Guha Mazumder DN: Chronic arsenic toxicity & human health. Indian J Med Res. 2008, 128: 436-447.","journal-title":"Indian J Med Res"},{"key":"605_CR5","first-page":"6975","volume":"66","author":"USEPA","year":"2001","unstructured":", : National primary drinking water regulations; arsenic and clarification to compliance and new source contaminants monitoring; final rule. Federal Register. 2001, 66: 6975-7066.","journal-title":"Federal Register"},{"key":"605_CR6","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1080\/10408440500534230","volume":"36","author":"SM Cohen","year":"2006","unstructured":"Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD: Methylated arsenicals: The implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Critical Reviews in Toxicology. 2006, 36: 99-133. 10.1080\/10408440500534230","journal-title":"Critical Reviews in Toxicology"},{"key":"605_CR7","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1007\/BF00343121","volume":"57","author":"M Vahter","year":"1985","unstructured":"Vahter M, Marafente E: Reduction and binding of arsenate in marmoset monkeys. Archives of Toxicology. 1985, 57: 119-124. 10.1007\/BF00343121","journal-title":"Archives of Toxicology"},{"key":"605_CR8","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1016\/j.taap.2008.12.016","volume":"235","author":"CH Tseng","year":"2009","unstructured":"Tseng CH: A review on environmental factors regulating arsenic methylation in humans. Toxicology and Applied Pharmacology. 2009, 235: 338-350. 10.1016\/j.taap.2008.12.016","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR9","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.taap.2006.10.006","volume":"222","author":"AD Kligerman","year":"2007","unstructured":"Kligerman AD, Tennant AH: Insights into the carcinogenic mode of action of arsenic. Toxicology and Applied Pharmacology. 2007, 222: 281-288. 10.1016\/j.taap.2006.10.006","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR10","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.taap.2004.05.017","volume":"201","author":"E Dopp","year":"2004","unstructured":"Dopp E, Hartmann LM, Florea AM, von Recklinghausen U, Pieper R, Shokouhi B, Rettenmeier AW, Hirner AV, Obe G: Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells. Toxicology and Applied Pharmacology. 2004, 201: 156-165. 10.1016\/j.taap.2004.05.017","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1093\/toxsci\/kfi218","volume":"87","author":"E Dopp","year":"2005","unstructured":"Dopp E, Hartmann LM, von Recklinghausen U, Florea AM, Rabieh S, Zimmermann U, Shokouhi B, Yadav S, Hirner AV, Rettenmeier AW: Forced uptake of trivalent and pentavalent methylated and inorganic arsenic and its cyto-\/genotoxicity in fibroblasts and hepatoma cells. Toxicological Sciences. 2005, 87: 46-56. 10.1093\/toxsci\/kfi218","journal-title":"Toxicological Sciences"},{"key":"605_CR12","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1093\/carcin\/bgg018","volume":"24","author":"T Schwerdtle","year":"2003","unstructured":"Schwerdtle T, Walter I, Mackiw I, Hartwig A: Induction of oxidative DNA damage by arsenite and its trivalent and pentavalent methylated metabolites in cultured human cells and isolated DNA. Carcinogenesis. 2003, 24: 967-974. 10.1093\/carcin\/bgg018","journal-title":"Carcinogenesis"},{"key":"605_CR13","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1021\/tx0001878","volume":"14","author":"S Lin","year":"2001","unstructured":"Lin S, Del Razo LM, Styblo M, Wang CQ, Cullen WR, Thomas DJ: Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes. Chemical Research in Toxicology. 2001, 14: 305-311. 10.1021\/tx0001878","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.mrfmmm.2003.07.009","volume":"533","author":"TG Rossman","year":"2003","unstructured":"Rossman TG: Mechanism of arsenic carcinogenesis: an integrated approach. Mutat Res. 2003, 533: 37-65. 10.1016\/j.mrfmmm.2003.07.009","journal-title":"Mutat Res"},{"key":"605_CR15","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.bbrc.2006.10.054","volume":"351","author":"ZJ Liu","year":"2006","unstructured":"Liu ZJ, Sanchez MA, Jiang X, Boles E, Landfear SM, Rosen BP: Mammalian glucose permease GLUT1 facilitates transport of arsenic trioxide and methylarsonous acid. Biochemical and Biophysical Research Communications. 2006, 351: 424-430. 10.1016\/j.bbrc.2006.10.054","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"605_CR16","doi-asserted-by":"publisher","first-page":"6053","DOI":"10.1073\/pnas.092131899","volume":"99","author":"ZJ Liu","year":"2002","unstructured":"Liu ZJ, Shen J, Carbrey JM, Mukhopadhyay R, Agre P, Rosen BP: Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proceedings of the National Academy of Sciences of the United States of America. 2002, 99: 6053-6058. 10.1073\/pnas.092131899","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"605_CR17","doi-asserted-by":"crossref","first-page":"F685","DOI":"10.1152\/ajprenal.1999.277.5.F685","volume":"277","author":"H Tsukaguchi","year":"1999","unstructured":"Tsukaguchi H, Weremowicz S, Morton CC, Hediger MA: Functional and molecular characterization of the human neutral solute channel aquaporin-9. American Journal of Physiology-Renal Physiology. 1999, 277: F685-F696.","journal-title":"American Journal of Physiology-Renal Physiology"},{"key":"605_CR18","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00204-009-0499-7","volume":"84","author":"Z Drobna","year":"2010","unstructured":"Drobna Z, Walton FS, Paul DS, Xing WB, Thomas DJ, Styblo M: Metabolism of arsenic in human liver: the role of membrane transporters. Archives of Toxicology. 2010, 84: 3-16. 10.1007\/s00204-009-0499-7","journal-title":"Archives of Toxicology"},{"key":"605_CR19","volume-title":"Toxicol Appl Pharmacol","author":"DJ Thomas","year":"2007","unstructured":"Thomas DJ: Molecular processes in cellular arsenic metabolism. Toxicol Appl Pharmacol. 2007,"},{"key":"605_CR20","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1021\/tx0342060","volume":"17","author":"SV Kala","year":"2004","unstructured":"Kala SV, Kala G, Prater CI, Sartorelli AC, Lieberman MW: Formation and urinary excretion of arsenic triglutathione and methylarsenic diglutathione. Chemical Research in Toxicology. 2004, 17: 243-249. 10.1021\/tx0342060","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR21","doi-asserted-by":"publisher","first-page":"33404","DOI":"10.1074\/jbc.M007030200","volume":"275","author":"SV Kala","year":"2000","unstructured":"Kala SV, Neely MW, Kala G, Prater CI, Atwood DW, Rice JS, Lieberman MW: The MRP2\/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic. Journal of Biological Chemistry. 2000, 275: 33404-33408. 10.1074\/jbc.M007030200","journal-title":"Journal of Biological Chemistry"},{"key":"605_CR22","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.etap.2006.07.010","volume":"23","author":"Y Kobayashi","year":"2007","unstructured":"Kobayashi Y, Hayakawa T, Hirano S: Expression and activity of arsenic methyltransferase Cyt19 in rat tissues. Environmental Toxicology and Pharmacology. 2007, 23: 115-120. 10.1016\/j.etap.2006.07.010","journal-title":"Environmental Toxicology and Pharmacology"},{"key":"605_CR23","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1002\/(SICI)1520-670X(2000)13:1<173::AID-JTRA18>3.0.CO;2-T","volume":"13","author":"M Vahter","year":"2000","unstructured":"Vahter M, Concha G, Nermell B: Factors influencing arsenic methylation in humans. Journal of Trace Elements in Experimental Medicine. 2000, 13: 173-184. 10.1002\/(SICI)1520-670X(2000)13:1<173::AID-JTRA18>3.0.CO;2-T.","journal-title":"Journal of Trace Elements in Experimental Medicine"},{"key":"605_CR24","doi-asserted-by":"publisher","first-page":"7364","DOI":"10.1074\/jbc.M512227200","volume":"281","author":"TC Wood","year":"2006","unstructured":"Wood TC, Salavagionne OE, Mukherjee B, Wang LW, Klumpp AF, Thomae BA, Eckloff BW, Schaid DJ, Wieben ED, Weinshilboum RM: Human arsenic methyltransferase (AS3MT) pharmacogenetics - Gene resequencing and functional genomics studies. Journal of Biological Chemistry. 2006, 281: 7364-7373. 10.1074\/jbc.M512227200","journal-title":"Journal of Biological Chemistry"},{"key":"605_CR25","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1021\/tx060076u","volume":"19","author":"Z Drobna","year":"2006","unstructured":"Drobna Z, Xing WB, Thomas DJ, Styblo M: shRNA silencing of AS3MT expression minimizes arsenic methylation capacity of HepG2 cells. Chemical Research in Toxicology. 2006, 19: 894-898. 10.1021\/tx060076u","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR26","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.taap.2003.10.020","volume":"198","author":"DJ Thomas","year":"2004","unstructured":"Thomas DJ, Waters SB, Styblo M: Elucidating the pathway for arsenic methylation. Toxicology and Applied Pharmacology. 2004, 198: 319-326. 10.1016\/j.taap.2003.10.020","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR27","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s00204-004-0620-x","volume":"79","author":"T Hayakawa","year":"2005","unstructured":"Hayakawa T, Kobayashi Y, Cui X, Hirano S: A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19. Archives of Toxicology. 2005, 79: 183-191. 10.1007\/s00204-004-0620-x","journal-title":"Archives of Toxicology"},{"key":"605_CR28","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1021\/tx060053f","volume":"19","author":"H Naranmandura","year":"2006","unstructured":"Naranmandura H, Suzuki N, Suzuki KT: Trivalent arsenicals are bound to proteins during reductive methylation. Chemical Research in Toxicology. 2006, 19: 1010-1018. 10.1021\/tx060053f","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR29","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1021\/tx0342161","volume":"17","author":"SB Waters","year":"2004","unstructured":"Waters SB, Devesa V, Del Razo LM, Styblo M, Thomas DJ: Endogenous reductants support the catalytic function of recombinant rat Cyt19, an arsenic methyltransferase. Chemical Research in Toxicology. 2004, 17: 404-409. 10.1021\/tx0342161","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR30","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1089\/ars.2005.7.385","volume":"7","author":"M Kobayashi","year":"2005","unstructured":"Kobayashi M, Yamamoto M: Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxidants & Redox Signaling. 2005, 7: 385-394. 10.1089\/ars.2005.7.385","journal-title":"Antioxidants & Redox Signaling"},{"key":"605_CR31","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1002\/mc.20465","volume":"48","author":"WG Li","year":"2009","unstructured":"Li WG, Kong AN: Molecular Mechanisms of Nrf2-Mediated Antioxidant Response. Molecular Carcinogenesis. 2009, 48: 91-104. 10.1002\/mc.20465","journal-title":"Molecular Carcinogenesis"},{"key":"605_CR32","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.taap.2008.03.003","volume":"230","author":"XJ Wang","year":"2008","unstructured":"Wang XJ, Sun Z, Chen WM, Li YJ, Villeneuve NF, Zhang DD: Activation of Nrf2 by arsenite and monomethylarsonous acid is independent of Keap1-C151: enhanced Keap1-Cul3 interaction. Toxicology and Applied Pharmacology. 2008, 230: 383-389. 10.1016\/j.taap.2008.03.003","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR33","doi-asserted-by":"publisher","first-page":"23620","DOI":"10.1074\/jbc.M604120200","volume":"281","author":"XQ He","year":"2006","unstructured":"He XQ, Chen MG, Lin GX, Ma Q: Arsenic induces NAD(P)H-quinone oxidoreductase I by disrupting the Nrf2 center dot Keap1 center dot CuI3 complex and recruiting Nrf2 center dot Maf to the antioxidant response element enhancer. Journal of Biological Chemistry. 2006, 281: 23620-23631. 10.1074\/jbc.M604120200","journal-title":"Journal of Biological Chemistry"},{"key":"605_CR34","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1023\/A:1020248922689","volume":"29","author":"MR Easterling","year":"2002","unstructured":"Easterling MR, Styblo M, Evans MV, Kenyon EM: Pharmacokinetic modeling of arsenite uptake and metabolism in hepatocytes - Mechanistic insights and implications for further experiments. Journal of Pharmacokinetics and Pharmacodynamics. 2002, 29: 207-234. 10.1023\/A:1020248922689","journal-title":"Journal of Pharmacokinetics and Pharmacodynamics"},{"key":"605_CR35","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S0955-0674(03)00017-6","volume":"15","author":"JJ Tyson","year":"2003","unstructured":"Tyson JJ, Chen KC, Novak B: Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. Current Opinion in Cell Biology. 2003, 15: 221-231. 10.1016\/S0955-0674(03)00017-6","journal-title":"Current Opinion in Cell Biology"},{"key":"605_CR36","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.tiv.2008.11.011","volume":"23","author":"ZF Miao","year":"2009","unstructured":"Miao ZF, Chang EE, Tsai FY, Yeh SC, Wu CF, Wu KY, Wang CJ, Tsou TC: Increased aquaglyceroporin 9 expression disrupts arsenic resistance in human lung cancer cells. Toxicology in Vitro. 2009, 23: 209-216. 10.1016\/j.tiv.2008.11.011","journal-title":"Toxicology in Vitro"},{"key":"605_CR37","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","volume":"117","author":"AL Hodgkin","year":"1952","unstructured":"Hodgkin AL, Huxley AF: A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952, 117: 500-544.","journal-title":"J Physiol"},{"key":"605_CR38","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.jinorgbio.2007.10.021","volume":"102","author":"KT Kitchin","year":"2008","unstructured":"Kitchin KT, Wallace K: The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. Journal of Inorganic Biochemistry. 2008, 102: 532-539. 10.1016\/j.jinorgbio.2007.10.021","journal-title":"Journal of Inorganic Biochemistry"},{"key":"605_CR39","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1002\/(SICI)1520-6866(1999)19:6<385::AID-TCM3>3.0.CO;2-V","volume":"19","author":"KT Kitchin","year":"1999","unstructured":"Kitchin KT, Del Razo LM, Brown JL, Anderson WL, Kenyon EM: An integrated pharmacokinetic and pharmacodynamic study of arsenite action. 1. Heme oxygenase induction in rats. Teratogenesis Carcinogenesis and Mutagenesis. 1999, 19: 385-402. 10.1002\/(SICI)1520-6866(1999)19:6<385::AID-TCM3>3.0.CO;2-V.","journal-title":"Teratogenesis Carcinogenesis and Mutagenesis"},{"key":"605_CR40","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1016\/j.febslet.2006.02.031","volume":"580","author":"Y Shinkai","year":"2006","unstructured":"Shinkai Y, Sumi D, Fukami I, Ishii T, Kumagai Y: Sulforaphane, an activator of Nrf2, suppresses cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes. Febs Letters. 2006, 580: 1771-1774. 10.1016\/j.febslet.2006.02.031","journal-title":"Febs Letters"},{"key":"605_CR41","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1042\/BJ20051518","volume":"395","author":"V Vollrath","year":"2006","unstructured":"Vollrath V, Wielandt AM, Iruretagoyena M, Chianale J: Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochemical Journal. 2006, 395: 599-609. 10.1042\/BJ20051518","journal-title":"Biochemical Journal"},{"key":"605_CR42","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1124\/jpet.109.152033","volume":"330","author":"AK Abraham","year":"2009","unstructured":"Abraham AK, Mager DE, Gao X, Li M, Healy DR, Maurer TS: Mechanism-Based Pharmacokinetic\/Pharmacodynamic Model of Parathyroid Hormone-Calcium Homeostasis in Rats and Humans. Journal of Pharmacology and Experimental Therapeutics. 2009, 330: 169-178. 10.1124\/jpet.109.152033","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"605_CR43","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1093\/toxsci\/67.2.159","volume":"67","author":"R Sarangapani","year":"2002","unstructured":"Sarangapani R, Teeguarden J, Plotzke KP, McKim JM, Andersen ME: Dose-response modeling of cytochrome P450 induction in rats by octamethylcyclotetrasiloxane. Toxicological Sciences. 2002, 67: 159-172. 10.1093\/toxsci\/67.2.159","journal-title":"Toxicological Sciences"},{"key":"605_CR44","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1007\/s10928-007-9075-z","volume":"35","author":"HA El-Masri","year":"2008","unstructured":"El-Masri HA, Kenyon EM: Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites. J Pharmacokinet Pharmacodyn. 2008, 35: 31-68. 10.1007\/s10928-007-9075-z","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"605_CR45","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1006\/taap.1996.0244","volume":"140","author":"S Mann","year":"1996","unstructured":"Mann S, Droz PO, Vahter M: A physiologically based pharmacokinetic model for arsenic exposure .2. Validation and application in humans. Toxicology and Applied Pharmacology. 1996, 140: 471-486. 10.1006\/taap.1996.0244","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR46","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1006\/rtph.1999.1282","volume":"29","author":"DH Yu","year":"1999","unstructured":"Yu DH: A physiologically based pharmacokinetic model of inorganic arsenic. Regulatory Toxicology and Pharmacology. 1999, 29: 128-141. 10.1006\/rtph.1999.1282","journal-title":"Regulatory Toxicology and Pharmacology"},{"key":"605_CR47","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/S0022-2836(65)80285-6","volume":"12","author":"J Monod","year":"1965","unstructured":"Monod J, Wyman J, Changeux JP: On the Nature of Allosteric Transitions: A Plausible Model. J Mol Biol. 1965, 12: 88-118. 10.1016\/S0022-2836(65)80285-6","journal-title":"J Mol Biol"},{"key":"605_CR48","doi-asserted-by":"crossref","first-page":"5788","DOI":"10.1016\/S0021-9258(18)62721-8","volume":"245","author":"C Frieden","year":"1970","unstructured":"Frieden C: Kinetic aspects of regulation of metabolic processes. The hysteretic enzyme concept. J Biol Chem. 1970, 245: 5788-5799.","journal-title":"J Biol Chem"},{"key":"605_CR49","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1093\/toxsci\/kfn257","volume":"107","author":"DJ Thomas","year":"2009","unstructured":"Thomas DJ: Unraveling Arsenic-EFGlutathione Connections. Toxicological Sciences. 2009, 107: 309-311. 10.1093\/toxsci\/kfn257","journal-title":"Toxicological Sciences"},{"key":"605_CR50","doi-asserted-by":"publisher","first-page":"32700","DOI":"10.1074\/jbc.M404912200","volume":"279","author":"EM Leslie","year":"2004","unstructured":"Leslie EM, Haimeur A, Waalkes MP: Arsenic transport by the human multidrug resistance protein 1 (MRP1\/ABCC1) - Evidence that a tri-glutathione conjugate is required. Journal of Biological Chemistry. 2004, 279: 32700-32708. 10.1074\/jbc.M404912200","journal-title":"Journal of Biological Chemistry"},{"key":"605_CR51","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1021\/tx990050l","volume":"12","author":"M Styblo","year":"1999","unstructured":"Styblo M, Del Razo LM, LeCluyse EL, Hamilton GA, Wang CQ, Cullen WR, Thomas DJ: Metabolism of arsenic in primary cultures of human and rat hepatocytes. Chemical Research in Toxicology. 1999, 12: 560-565. 10.1021\/tx990050l","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR52","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1073\/pnas.0510220103","volume":"103","author":"BS Gutkin","year":"2006","unstructured":"Gutkin BS, Dehaene S, Changeux JP: A neurocomputational hypothesis for nicotine addiction. Proceedings of the National Academy of Sciences of the United States of America. 2006, 103: 1106-1111. 10.1073\/pnas.0510220103","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"605_CR53","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.taap.2004.05.004","volume":"201","author":"Z Drobna","year":"2004","unstructured":"Drobna Z, Waters SB, Walton FS, LeCluyse EL, Thomas DJ, Styblo M: Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes. Toxicology and Applied Pharmacology. 2004, 201: 166-177. 10.1016\/j.taap.2004.05.004","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR54","volume-title":"Version 32","author":"SIMLAB","year":"2009","unstructured":", : Simulation Environment for Uncertainty and Sensitivity Analysis, developed by the Joint Research Centre of the European Commission. Version 32. 2009,"},{"key":"605_CR55","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1083\/jcb.115.2.485","volume":"115","author":"OA Weisz","year":"1991","unstructured":"Weisz OA, Schnaar RL: Hepatocyte Adhesion to Carbohydrate-Derivatized Surfaces .1. Surface-Topography of the Rat Hepatic Lectin. Journal of Cell Biology. 1991, 115: 485-493. 10.1083\/jcb.115.2.485","journal-title":"Journal of Cell Biology"},{"key":"605_CR56","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1124\/dmd.107.019034","volume":"36","author":"E Dopp","year":"2008","unstructured":"Dopp E, von Recklinghausen U, Hartmann LM, Stueckradt I, Pollok I, Rabieh S, Hao L, Nussler A, Katier C, Hirner AV, Rettenmeier AW: Subcellular distribution of inorganic and methylated arsenic compounds in human urothelial cells and human hepatocytes. Drug Metabolism and Disposition. 2008, 36: 971-979. 10.1124\/dmd.107.019034","journal-title":"Drug Metabolism and Disposition"},{"key":"605_CR57","volume-title":"Proceedings of the 1997 Winter Simulation Conference","author":"K Chan","year":"1997","unstructured":"Chan K, Saltelli A, Tarantola S: Sensitivity analysis of model output: Variance-based methods make the difference. Proceedings of the 1997 Winter Simulation Conference. 1997,"},{"key":"605_CR58","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/00401706.1999.10485594","volume":"41","author":"A Saltelli","year":"1999","unstructured":"Saltelli A, Tarantola S, Chan KPS: A quantitative model-independent method for global sensitivity analysis of model output. Technometrics. 1999, 41: 39-56. 10.2307\/1270993.","journal-title":"Technometrics"},{"key":"605_CR59","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1289\/ehp.02110s6971","volume":"110","author":"ME Andersen","year":"2002","unstructured":"Andersen ME, Yang RSH, French CT, Chubb LS, Dennison JE: Molecular circuits, biological switches, and nonlinear dose-response relationships. Environmental Health Perspectives. 2002, 110: 971-978. 10.1289\/ehp.110-a444","journal-title":"Environmental Health Perspectives"},{"key":"605_CR60","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1126\/science.280.5365.895","volume":"280","author":"JE Ferrell","year":"1998","unstructured":"Ferrell JE, Machleder EM: The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. Science. 1998, 280: 895-898. 10.1126\/science.280.5365.895","journal-title":"Science"},{"key":"605_CR61","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1006\/taap.1996.8066","volume":"144","author":"ME Andersen","year":"1997","unstructured":"Andersen ME, Eklund CR, Mills JJ, Barton HA, Birnbaum LS: A multicompartment geometric model of the liver in relation to regional induction of cytochrome P450s. Toxicology and Applied Pharmacology. 1997, 144: 135-144. 10.1006\/taap.1996.8066","journal-title":"Toxicology and Applied Pharmacology"},{"key":"605_CR62","doi-asserted-by":"publisher","first-page":"10840","DOI":"10.1073\/pnas.0604085103","volume":"103","author":"S Krishna","year":"2006","unstructured":"Krishna S, Jensen MH, Sneppen K: Minimal model of spiky oscillations in NF-kappa B signaling. Proceedings of the National Academy of Sciences of the United States of America. 2006, 103: 10840-10845. 10.1073\/pnas.0604085103","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"605_CR63","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1093\/toxsci\/kfn192","volume":"107","author":"JGM Ortiz","year":"2009","unstructured":"Ortiz JGM, Opoka R, Kane D, Cartwright IL: Investigating Arsenic Susceptibility from a Genetic Perspective in Drosophila Reveals a Key Role for Glutathione Synthetase. Toxicological Sciences. 2009, 107: 416-426. 10.1093\/toxsci\/kfn192","journal-title":"Toxicological Sciences"},{"key":"605_CR64","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1021\/tx800128d","volume":"21","author":"KL Munro","year":"2008","unstructured":"Munro KL, Mariana A, Klavins AI, Foster AJ, Lai B, Vogo S, Cai Z, Harris HH, Dillon CT: Microprobe XRF mapping and XAS investigations of the intracellular metabolism of arsenic for understanding arsenic-induced toxicity. Chemical Research in Toxicology. 2008, 21: 1760-1769. 10.1021\/tx800128d","journal-title":"Chemical Research in Toxicology"},{"key":"605_CR65","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1093\/toxsci\/kfh265","volume":"82","author":"X Cui","year":"2004","unstructured":"Cui X, Kobayashi Y, Hayakawa T, Hirano S: Arsenic speciation in bile and urine following oral and intravenous exposure to inorganic and organic arsenics in rats. Toxicological Sciences. 2004, 82: 478-487. 10.1093\/toxsci\/kfh265","journal-title":"Toxicological Sciences"},{"key":"605_CR66","first-page":"3","volume":"232","author":"DJ Thomas","year":"2007","unstructured":"Thomas DJ, Li JX, Waters SB, Xing WB, Adair BM, Drobna Z, Devesa V, Styblo M: Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Experimental Biology and Medicine. 2007, 232: 3-13.","journal-title":"Experimental Biology and Medicine"},{"key":"605_CR67","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1016\/j.freeradbiomed.2004.06.040","volume":"37","author":"TP Dalton","year":"2004","unstructured":"Dalton TP, Chen Y, Schneider SN, Nebert DW, Shertzer HG: Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology and Medicine. 2004, 37: 1511-1526. 10.1016\/j.freeradbiomed.2004.06.040","journal-title":"Free Radical Biology and Medicine"},{"key":"605_CR68","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1371\/journal.pcbi.0030189","volume":"3","author":"RN Gutenkunst","year":"2007","unstructured":"Gutenkunst RN, Waterfall JJ, Casey FP, Brown KS, Myers CR, Sethna JP: Universally sloppy parameter sensitivities in systems biology models. Plos Computational Biology. 2007, 3: 1871-1878. 10.1371\/journal.pcbi.0030189","journal-title":"Plos Computational Biology"},{"key":"605_CR69","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.yrtph.2007.10.012","volume":"50","author":"RA Clewell","year":"2008","unstructured":"Clewell RA, Clewell HJ: Development and specification of physiologically based pharmacokinetic models for use in risk assessment. Regulatory Toxicology and Pharmacology. 2008, 50: 129-143. 10.1016\/j.yrtph.2007.10.012","journal-title":"Regulatory Toxicology and Pharmacology"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-5-16.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T06:24:44Z","timestamp":1630477484000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-5-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,1,25]]},"references-count":69,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["605"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-5-16","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,1,25]]},"assertion":[{"value":"16 February 2010","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"16"}}