{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:40:46Z","timestamp":1790685646663,"version":"4.1.0"},"reference-count":41,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2000,6,1]],"date-time":"2000-06-01T00:00:00Z","timestamp":959817600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hum Exp Toxicol"],"published-print":{"date-parts":[[2000,6]]},"abstract":"<jats:p>\n                    In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability ofthe HepG2 cells they were cultured in 4-32 jiM copper(II) sulphate (CuS04)). These levels were comparable to the circulatory and tissue concentrations of copper recorded for these two diseases. Specific uptake comparable to levels of copper recorded in the livers of patients with Wilson's disease and ICC was measured in the HepG2 cells. After 48 h acid vesicle function increased from 4 to 32 jiM Cu\n                    <jats:sup>2<\/jats:sup>\n                    + but significantly declined at 64 MM compared to the controls. Lysosomal acid phosphatase showed a concen-tration dependent decline in activity at 72 h. Introduction Copper is a potent catalyst of processes generating reactive oxygen intermediates and its cellular up-take, transport and excretion are therefore tightly controlled. Elevated hepatic copper concentrations are associated with liver damage in Wilson's disease\n                    <jats:sup>2<\/jats:sup>\n                    , in Indian childhood cirrhosis\n                    <jats:sup>3<\/jats:sup>\n                    (ICC), and in other copper-related cirrhoses of infancy. Nevertheless, the cellular consequences of copper toxicity remain to be understood in the context of the disease pathology. In Wilson's disease, biliary excretion of copper is impaired by mutations in a trans-Golgi P-type ATPase\n                    <jats:sup>4<\/jats:sup>\n                    resulting in intracellular hepatic copper accumulation\n                    <jats:sup>5<\/jats:sup>\n                    with progressive dysfunction, fibrosis, and liver failure. However, clinical variability of Wilson's disease and the lack of a clear genotype\/ Cellls exposed to 64 MM Cu\n                    <jats:sup>2<\/jats:sup>\n                    + had a potential doubling time (Tpot) 21 h longer than the control cells due to a prolonged DNA synthesis phase. At 64 jiM Cu\n                    <jats:sup>2<\/jats:sup>\n                    +, increases of necrosis up to 18% were seen whereas comparable levels ofapoptotic and necrotic cells (&lt; 5%) were seen below this concentration. Chronic exposure over 8 weeks impaired colony-forming effi-ciency at concentrations of 16 MM Cu\n                    <jats:sup>2<\/jats:sup>\n                    + and above. This study suggests that when liver cells sequester large amounts of copper, the toxic effects include delayed cell-cycle progression, a gradual loss of replicative capacity, and an increased incidence of cell death.\n                  <\/jats:p>","DOI":"10.1191\/096032700678815963","type":"journal-article","created":{"date-parts":[[2003,4,3]],"date-time":"2003-04-03T19:38:43Z","timestamp":1049398723000},"page":"367-376","source":"Crossref","is-referenced-by-count":72,"title":["Copper toxicity affects proliferation and viability of human hepatoma cells                 (HepG2 line)"],"prefix":"10.1177","volume":"19","author":[{"given":"N S","family":"Aston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Watt","sequence":"additional","affiliation":[{"name":"University Division of Child Health, Stephenson Unit, The                         Children's Hospital, Sheffield, S10 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I E","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sheffield, Western Bank,                         Sheffield, S10 2TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M S","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G S","family":"Evans","sequence":"additional","affiliation":[{"name":"University Division of Child Health, Stephenson Unit, The                         Children's Hospital, Sheffield, S10 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2000,6,1]]},"reference":[{"key":"atypb1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nu.15.070195.001453"},{"key":"atypb2","first-page":"167","volume-title":"Diseases of the Liver and Biliary System in Children","author":"Tanner MS","year":"1999"},{"key":"atypb3","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/67.5.1074S"},{"key":"atypb4","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007221"},{"key":"atypb5","unstructured":"5                      Danks DM                 . Disorders of copper transport. In: The Metabolic and                     Molecular Basis of Inherited Disease, (                     Shriver CR                 ,                      Beaudet AL                 ,                      Sly WS                 ,                      Valle D                 , Eds), 7th edn., Vol. 2.                      McGraw-Hill America                 , 1995, pp. 2211-2237."},{"key":"atypb6","doi-asserted-by":"publisher","DOI":"10.1097\/00005176-198707000-00013"},{"key":"atypb7","doi-asserted-by":"publisher","DOI":"10.1136\/gut.24.8.767"},{"key":"atypb8","doi-asserted-by":"publisher","DOI":"10.1007\/BF00239315"},{"key":"atypb9","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1998.00292.x"},{"key":"atypb10","first-page":"684","volume":"390","author":"Brown DR","year":"1998","journal-title":"The cellular prion protein binds copper in vivo Nature"},{"key":"atypb11","doi-asserted-by":"publisher","DOI":"10.1007\/BF02628826"},{"key":"atypb12","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.990110204"},{"key":"atypb13","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(08)62312-8"},{"key":"atypb14","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/S0016-5085(87)91085-7","volume":"92","author":"Lake JR","year":"1987","journal-title":"Gastroenterology"},{"key":"atypb15","doi-asserted-by":"publisher","DOI":"10.1177\/23.6.239053"},{"key":"atypb16","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.66.1.188"},{"key":"atypb17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.18.5573"},{"key":"atypb18","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.990090618"},{"key":"atypb19","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.990060618"},{"key":"atypb20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.14.7481"},{"key":"atypb21","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-364931-7.50011-2"},{"key":"atypb22","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9975(80)90058-4"},{"key":"atypb23","first-page":"1","volume":"33","author":"Hayashi H","year":"1975","journal-title":"Lab Invest"},{"key":"atypb24","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)91693-8"},{"key":"atypb25","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/117.1.19"},{"key":"atypb26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113873"},{"key":"atypb27","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)91080-2"},{"key":"atypb28","first-page":"405","volume":"38","author":"Costa M","year":"1982","journal-title":"Res Commun Chem Pathol Pharmacol"},{"key":"atypb29","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(94)00177-7"},{"key":"atypb30","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S1016-8478(23)13378-4","volume":"7","author":"Kang JH","year":"1997","journal-title":"Mol Cells"},{"key":"atypb31","first-page":"1267","volume":"56","author":"Nair J","year":"1996","journal-title":"Cancer Res"},{"key":"atypb32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.1993.tb00168.x"},{"issue":"3","key":"atypb33","first-page":"A181","volume":"41","author":"Watt NT","year":"1997","journal-title":"Gut"},{"key":"atypb34","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/17.10.2157"},{"key":"atypb35","doi-asserted-by":"publisher","DOI":"10.1097\/00005176-199501000-00006"},{"key":"atypb36","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114333"},{"key":"atypb37","doi-asserted-by":"publisher","DOI":"10.1038\/37022"},{"key":"atypb38","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(95)90032-2"},{"key":"atypb39","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510280324"},{"key":"atypb40","doi-asserted-by":"publisher","DOI":"10.1038\/nm0598-588"},{"key":"atypb41","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(94)80232-7"}],"container-title":["Human &amp; Experimental Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1191\/096032700678815963","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1191\/096032700678815963","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:47:10Z","timestamp":1777448830000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1191\/096032700678815963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,6]]},"references-count":41,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2000,6]]}},"alternative-id":["10.1191\/096032700678815963"],"URL":"https:\/\/doi.org\/10.1191\/096032700678815963","relation":{},"ISSN":["0960-3271","1477-0903"],"issn-type":[{"value":"0960-3271","type":"print"},{"value":"1477-0903","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,6]]}}}