{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:11:57Z","timestamp":1790885517591,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":4201,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007273","name":"Comisi\u00f3n Interministerial de Ciencia y Tecnolog\u00eda","doi-asserted-by":"crossref","award":["SAF 97-0015"],"award-info":[{"award-number":["SAF 97-0015"]}],"id":[{"id":"10.13039\/501100007273","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Generalitat Valenciana (both to J.S.)","award":["GV01-137"],"award-info":[{"award-number":["GV01-137"]}]},{"name":"Ministerio de Educaci\u00f3n y Ciencia (to J.V.)","award":["BFI 2001-2849"],"award-info":[{"award-number":["BFI 2001-2849"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,3]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The findings of the current study indicate that UDCA partially prevents hepatic and mitochondrial glutathione depletion and oxidation resulting from chronic cholestasis. Impairment of biliary excretion was accompanied by decreased steady-state hepatic levels of \u03b3-glutamyl cysteine synthetase and \u03b3-cystathionase messenger RNAs. UDCA treatment led to up-regulation of \u03b3-glutamyl cysteine synthetase in animals with secondary biliary cirrhosis and prevented the marked increases in mitochondrial peroxide production and hydroxynonenal-protein adduct production that are observed during chronic cholestasis. A population of damaged and primarily apoptotic hepatocytes characterized by dramatic decreases in mitochondrial cardiolipin levels and membrane potential as well as phosphatidylserine exposure evolves in secondary biliary cirrhosis. UDCA treatment prevents the growth of this population along with the decreases in mitochondrial cardiolipin levels and membrane potential that are induced by chronic cholestasis. In conclusion, UDCA treatment enhances the antioxidant defense mediated by glutathione; in doing so, this treatment prevents cardiolipin depletion and cell injury in animals with secondary biliary cirrhosis. (Hepatology 2004;39:711-720)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.20101","type":"journal-article","created":{"date-parts":[[2004,3,1]],"date-time":"2004-03-01T03:02:00Z","timestamp":1078110120000},"page":"711-720","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":122,"title":["Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress"],"prefix":"10.1097","volume":"39","author":[{"given":"Gaetano","family":"Serviddio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Pereda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico V.","family":"Pallard\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Carretero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consuelo","family":"Borras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Cutrin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Vendemiale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Poli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Vi\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R2-18-20241201","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1056\/NEJM199611213352107","article-title":"Primary biliary cirrhosis.","volume":"335","author":"Kaplan","year":"1996","journal-title":"N Engl J Med"},{"key":"R3-18-20241201","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1056\/NEJM199105303242204","article-title":"A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.","volume":"324","author":"Poupon","year":"1991","journal-title":"N Engl J Med"},{"key":"R4-18-20241201","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1034\/j.1600-0528.2002.017402.x","article-title":"Primary biliary cirrhosis: an orchestrated immune response against epithelial cells.","volume":"174","author":"Gershwin","year":"2000","journal-title":"Immunol Rev"},{"key":"R5-18-20241201","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1016\/0016-5085(95)90585-5","article-title":"Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.","volume":"109","author":"Sokol","year":"1995","journal-title":"Gastroenterology"},{"key":"R6-18-20241201","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1002\/hep.1840120307","article-title":"Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes.","volume":"12","author":"Galle","year":"1990","journal-title":"HEPATOLOGY"},{"key":"R8-18-20241201","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1046\/j.1471-4159.1994.62010376.x","article-title":"Oxidative stress induces apoptosis in embryonic cortical neurons.","volume":"62","author":"Ratan","year":"1994","journal-title":"J Neurochem"},{"key":"R9-18-20241201","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/0006-2952(95)00233-P","article-title":"Inhibition of apoptosis by antioxidants in the human HL-60 leukemia cell line.","volume":"50","author":"Verhaegen","year":"1995","journal-title":"Biochem Pharmacol"},{"key":"R10-18-20241201","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1172\/JCI1325","article-title":"A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation.","volume":"101","author":"Rodrigues","year":"1998","journal-title":"J Clin Invest"},{"key":"R11-18-20241201","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/BF03401914","article-title":"Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production.","volume":"4","author":"Rodrigues","year":"1998","journal-title":"Mol Med"},{"key":"R12-18-20241201","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S0016-5085(98)70644-4","article-title":"Vitamin E reduces oxidant injury to mitochondria and the hepatotoxicity of taurochenodeoxycholic acid in the rat.","volume":"114","author":"Sokol","year":"1998","journal-title":"Gastroenterology"},{"key":"R13-18-20241201","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1203\/00006450-199809000-00022","article-title":"Effect of oxypurinol, a xanthine oxidase inhibitor, on hepatic injury in the bile duct-ligated rat.","volume":"44","author":"Sokol","year":"1998","journal-title":"Pediatr Res"},{"key":"R14-18-20241201","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/S0891-5849(97)00330-4","article-title":"Evidence for accelerated generation of hydroxyl radicals in experimental obstructive jaundice of rats.","volume":"24","author":"Tsai","year":"1998","journal-title":"Free Radic Biol Med"},{"key":"R15-18-20241201","first-page":"471","article-title":"Toxicity of bile acids on the electron transport chain of isolated rat liver mitochondria.","volume":"19","author":"Krahenbuhl","year":"1994","journal-title":"HEPATOLOGY"},{"key":"R16-18-20241201","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0005-2728(96)00041-2","article-title":"The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death.","volume":"1275","author":"Bernardi","year":"1996","journal-title":"Biochim Biophys Acta"},{"key":"R17-18-20241201","first-page":"930","article-title":"Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.","volume":"272","author":"Botla","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"R18-18-20241201","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1053\/jhep.2001.22702","article-title":"Bile acid-induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition.","volume":"33","author":"Yerushalmi","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R19-18-20241201","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S0168-8278(01)00092-7","article-title":"Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders.","volume":"35","author":"Lazaridis","year":"2001","journal-title":"J Hepatol"},{"key":"R20-18-20241201","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1016\/S0016-5085(97)70183-5","article-title":"Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.","volume":"113","author":"Poupon","year":"1997","journal-title":"Gastroenterology"},{"key":"R21-18-20241201","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1016\/0016-5085(93)90653-T","article-title":"Molecular aspects of membrane stabilization by ursodeoxycholate.","volume":"104","author":"Guldutuna","year":"1993","journal-title":"Gastroenterology"},{"key":"R22-18-20241201","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1053\/jhep.2001.24034","article-title":"Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.","volume":"33","author":"Beuers","year":"2001","journal-title":"HEPATOLOGY"},{"key":"R23-18-20241201","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1053\/jhep.2002.32533","article-title":"Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes.","volume":"35","author":"Qiao","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R24-18-20241201","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1006\/bbrc.1999.1403","article-title":"Ursodeoxycholic acid protects hepatocytes against oxidative injury via induction of antioxidants.","volume":"263","author":"Mitsuyoshi","year":"1999","journal-title":"Biochem Biophys Res Commun"},{"key":"R25-18-20241201","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1136\/gut.50.5.701","article-title":"Effect of ursodeoxycholic acid on methionine adenosyltransferase activity and hepatic glutathione metabolism in rats.","volume":"50","author":"Rodriguez-Ortigosa","year":"2002","journal-title":"Gut"},{"key":"R27-18-20241201","first-page":"305","article-title":"Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat.","volume":"65","author":"Kountouras","year":"1984","journal-title":"Br J Exp Pathol"},{"key":"R28-18-20241201","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1053\/jhep.2002.32969","article-title":"Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism.","volume":"35","author":"Minana","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R30-18-20241201","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0307-4412(83)90093-6","article-title":"A simple procedure to prepare isolated hepatocytes.","volume":"11","author":"Romero","year":"1983","journal-title":"Biochem Educ"},{"key":"R31-18-20241201","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/cyto.990150409","article-title":"A fast kinetic method for assessing mitochondrial membrane potential in isolated hepatocytes with rhodamine 123 and flow cytometry.","volume":"15","author":"Juan","year":"1994","journal-title":"Cytometry"},{"key":"R32-18-20241201","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1432-1033.1990.tb15632.x","article-title":"Analysis of the membrane potential of rat- and mouse-liver mitochondria by flow cytometry and possible applications.","volume":"194","author":"Petit","year":"1990","journal-title":"Eur J Biochem"},{"key":"R33-18-20241201","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/0006-291X(89)91700-2","article-title":"10-N nonyl-acridine orange: a fluorescent probe which stains mitochondria independently of their energetic state.","volume":"164","author":"Maftah","year":"1989","journal-title":"Biochem Biophys Res Commun"},{"key":"R34-18-20241201","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1042\/bj1700711","article-title":"Reaction of formiminoglutamate with liver glutamate dehydrogenase.","volume":"170","author":"Vina","year":"1978","journal-title":"Biochem J"},{"key":"R35-18-20241201","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1172\/JCI115286","article-title":"Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat.","volume":"88","author":"Lu","year":"1991","journal-title":"J Clin Invest"},{"key":"R36-18-20241201","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/oxfordjournals.jbchem.a130387","article-title":"Studies on the regulation of glutathione level in rat liver.","volume":"75","author":"Tateishi","year":"1974","journal-title":"J Biochem (Tokyo)"},{"key":"R37-18-20241201","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1074\/jbc.272.6.3346","article-title":"Oxidative stress, thiol reagents, and membrane potential modulate the mitochondrial permeability transition by affecting nucleotide binding to the adenine nucleotide translocase.","volume":"272","author":"Halestrap","year":"1997","journal-title":"J Biol Chem"},{"key":"R38-18-20241201","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0378-1119(01)00814-9","article-title":"Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage.","volume":"286","author":"Paradies","year":"2002","journal-title":"Gene"},{"key":"R39-18-20241201","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1016\/0016-5085(92)91187-9","article-title":"Antioxidant defenses in the bile duct-ligated rat.","volume":"103","author":"Singh","year":"1992","journal-title":"Gastroenterology"},{"key":"R40-18-20241201","first-page":"607","article-title":"Reduced antioxidative capacity in liver mitochondria from bile duct ligated rats.","volume":"22","author":"Krahenbuhl","year":"1995","journal-title":"HEPATOLOGY"},{"key":"R41-18-20241201","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0168-8278(94)80143-6","article-title":"Protective effect of S-adenosyl-L-methionine on liver damage induced by biliary obstruction in rats: a histological, ultrastructural and biochemical approach.","volume":"21","author":"Muriel","year":"1994","journal-title":"J Hepatol"},{"key":"R42-18-20241201","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/0016-5085(81)90489-3","article-title":"Evidence for impairment of transsulfuration pathway in cirrhosis.","volume":"81","author":"Horowitz","year":"1981","journal-title":"Gastroenterology"},{"key":"R43-18-20241201","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0166-3542(99)00041-8","article-title":"Interferonantioxidant combination therapy for chronic hepatitis Ca controlled pilot trial.","volume":"43","author":"Look","year":"1999","journal-title":"Antiviral Res"},{"key":"R44-18-20241201","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0168-8278(00)80122-1","article-title":"Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma.","volume":"33","author":"Avila","year":"2000","journal-title":"J Hepatol"},{"key":"R45-18-20241201","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF02150680","article-title":"Modulation of matrix Ca2 content by the ADPATP carrier in brown adipose tissue mitochondria. Influence of membrane lipid composition.","volume":"28","author":"Chavez","year":"1996","journal-title":"J Bioenerg Biomembr"},{"key":"R46-18-20241201","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/S0016-5085(98)70149-0","article-title":"Cholestasis confers resistance to the rat liver mitochondrial permeability transition.","volume":"115","author":"Lieser","year":"1998","journal-title":"Gastroenterology"},{"key":"R47-18-20241201","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1096\/fasebj.13.9.1055","article-title":"Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis: studies in vivo and in vitro.","volume":"13","author":"Esteve","year":"1999","journal-title":"FASEB J"},{"key":"R48-18-20241201","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1053\/jhep.2000.20240","article-title":"The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.","volume":"32","author":"Corpechot","year":"2000","journal-title":"HEPATOLOGY"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.20101","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200403000-00018","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T07:04:52Z","timestamp":1733036692000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200403000-00018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,3]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.20101","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2004,3]]}}}