{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:46:56Z","timestamp":1790930816909,"version":"4.1.0"},"reference-count":49,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[2000,4,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Liver\/kidney microsomal antibody type 1 (LKM1) is the marker of type 2 autoimmune hepatitis (AIH) and is detected in up to 6% of patients with hepatitis C virus (HCV) infection. It recognises linear and conformational epitopes of cytochrome P450IID6 (CYP2D6) and may have liver damaging activity, provided that CYP2D6 is accessible to effector mechanisms of autoimmune attack.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"methods\">\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>The presence of LKM1 in the plasma membrane was investigated by indirect immunofluorescence and confocal laser microscopy of isolated rat hepatocytes probed with 10 LKM1 positive sera (five from patients with AIH and five from patients with chronic HCV infection) and a rabbit polyclonal anti-CYP2D6 serum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Serum from both types of patient stained the plasma membrane of non-permeabilised cells, where the fluorescent signal could be visualised as discrete clumps. Conversely, permeabilised hepatocytes showed diffuse submembranous\/cytoplasmic staining. Adsorption with recombinant CYP2D6 substantially reduced plasma membrane staining and LKM1 immunoblot reactivity. Plasma membrane staining of LKM1 colocalised with that of anti-CYP2D6. Immunoprecipitation experiments showed that a single 50 kDa protein recognised by anti-CYP2D6 can be isolated from the plasma membrane of intact hepatocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>AIH and HCV related LKM1 recognise CYP2D6 exposed on the plasma membrane of isolated hepatocytes. This observation supports the notion that anti-CYP2D6 autoreactivity may be involved in the pathogenesis of liver damage.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gut.46.4.553","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T06:32:32Z","timestamp":1027751552000},"page":"553-561","source":"Crossref","is-referenced-by-count":101,"title":["Liver\/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane"],"prefix":"10.1136","volume":"46","author":[{"given":"L","family":"Muratori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Parola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Ripalti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Robino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Muratori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Bellomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Carini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Lenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M P","family":"Landini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Albano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F B","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2000,4,1]]},"reference":[{"key":"2025121302344994000_46.4.553.1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840070626"},{"key":"2025121302344994000_46.4.553.2","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007318"},{"key":"2025121302344994000_46.4.553.3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250308"},{"key":"2025121302344994000_46.4.553.4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510260305"},{"key":"2025121302344994000_46.4.553.5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1997.4131311.x"},{"key":"2025121302344994000_46.4.553.6","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1172\/JCI113949","article-title":"Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1.","volume":"83","author":"Manns","year":"1989","journal-title":"J Clin Invest"},{"key":"2025121302344994000_46.4.553.7","first-page":"108","article-title":"The time courses of intracellular transport of some secretory proteins of rat liver are not affected by an induced acute phase response.","volume":"60","author":"Myrset","year":"1993","journal-title":"Eur J Cell Biol"},{"key":"2025121302344994000_46.4.553.8","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(95)90210-4"},{"key":"2025121302344994000_46.4.553.9","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.1996.0415"},{"key":"2025121302344994000_46.4.553.10","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840150326"},{"key":"2025121302344994000_46.4.553.11","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1172\/JCI118936","article-title":"Antigenic targets in tienilic acid hepatitis. Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera.","volume":"98","author":"Robin","year":"1996","journal-title":"J Clin Invest"},{"key":"2025121302344994000_46.4.553.12","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0168-8278(97)82329-X","article-title":"Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis.","volume":"26","author":"Robin","year":"1997","journal-title":"J Hepatol"},{"key":"2025121302344994000_46.4.553.13","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0026-895X(25)09316-2","article-title":"Cytochrome P450 2E1 is a cell surface autoantigen in halothane hepatitis.","volume":"50","author":"Eliasson","year":"1996","journal-title":"Mol Pharmacol"},{"key":"2025121302344994000_46.4.553.14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840110521"},{"key":"2025121302344994000_46.4.553.15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0016-5085(93)90853-5","article-title":"Cytochromes P-450 in human hepatocyte plasma membrane: recognition by several autoantibodies.","volume":"104","author":"Loeper","year":"1993","journal-title":"Gastroenterology"},{"key":"2025121302344994000_46.4.553.16","first-page":"225","article-title":"Lack of surface expression for the B-cell autoepitope of cytochrome P450 IID6 evidenced by flow cytometry.","volume":"31","author":"Trautwein","year":"1993","journal-title":"Z Gastroenterol"},{"key":"2025121302344994000_46.4.553.17","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/j.1365-2249.1993.tb03409.x","article-title":"Cytochrome P450IID6 recognized by LKM1 antibody is not exposed on the surface of hepatocytes.","volume":"92","author":"Yamamoto","year":"1993","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.18","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1365-2249.1993.tb03406.x","article-title":"Type II autoimmune hepatitis: the conundrum of cytochrome P450IID6.","volume":"92","author":"Vergani","year":"1993","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840180435"},{"key":"2025121302344994000_46.4.553.20","first-page":"331","article-title":"Microsomal antibodies in active chronic hepatitis and other disorders.","volume":"15","author":"Rizzetto","year":"1973","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.21","doi-asserted-by":"publisher","DOI":"10.1136\/gut.37.3.406"},{"key":"2025121302344994000_46.4.553.22","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(97)80477-1"},{"key":"2025121302344994000_46.4.553.23","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.29.5.403"},{"key":"2025121302344994000_46.4.553.24","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1002\/hep.1840080632","article-title":"Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2.","volume":"8","author":"Martini","year":"1988","journal-title":"Hepatology"},{"key":"2025121302344994000_46.4.553.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(97)70104-5"},{"key":"2025121302344994000_46.4.553.26","unstructured":"Sambrook J Fritsh EF Maniatis T (1989) Molecular cloning. A laboratory manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor), 2nd edn.."},{"key":"2025121302344994000_46.4.553.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.21.8256"},{"key":"2025121302344994000_46.4.553.28","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(88)90134-2"},{"key":"2025121302344994000_46.4.553.29","first-page":"36","article-title":"Liver cell surface expression of the antigen reacting with liver-kidney microsomal antibody (LKM).","volume":"55","author":"Lenzi","year":"1984","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.30","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0031-6997(25)06832-2","article-title":"Drug metabolism and effects of carcinogens in cultured hepatic cells.","volume":"31","author":"Sirica","year":"1979","journal-title":"Pharmacol Rev"},{"key":"2025121302344994000_46.4.553.31","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/BF02796423","article-title":"Primary cultures and the levels of cytochrome P450 in hepatocytes from mouse, rat, hamster, and rabbit liver.","volume":"18","author":"Maslansky","year":"1982","journal-title":"In Vitro"},{"key":"2025121302344994000_46.4.553.32","doi-asserted-by":"publisher","DOI":"10.1124\/mol.54.1.8"},{"key":"2025121302344994000_46.4.553.33","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1365-2249.1994.tb06585.x","article-title":"Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection.","volume":"97","author":"Ma","year":"1994","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.34","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1016\/0016-5085(93)90657-X","article-title":"Characterization of anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera.","volume":"104","author":"Yamamoto","year":"1993","journal-title":"Gastroenterology"},{"key":"2025121302344994000_46.4.553.35","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1997.4071302.x"},{"key":"2025121302344994000_46.4.553.36","doi-asserted-by":"publisher","DOI":"10.1080\/004982597240497"},{"key":"2025121302344994000_46.4.553.37","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S1054-3589(08)60175-1","article-title":"Autoantibodies against cytochromes P450: role in human diseases.","volume":"30","author":"Beaune","year":"1994","journal-title":"Adv Pharmacol"},{"key":"2025121302344994000_46.4.553.38","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/S0168-8278(21)80002-1","article-title":"Role of reactive metabolises in drug-induced hepatitis.","volume":"23 (suppl 1)","author":"Pessayre","year":"1995","journal-title":"J Hepatol"},{"key":"2025121302344994000_46.4.553.39","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1055\/s-2007-1007281","article-title":"Molecular basis of drug-induced immunological liver injury.","volume":"15","author":"Van Pelt","year":"1995","journal-title":"Semin Liver Dis"},{"key":"2025121302344994000_46.4.553.40","doi-asserted-by":"publisher","DOI":"10.1124\/mol.55.2.223"},{"key":"2025121302344994000_46.4.553.41","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1993.1180"},{"key":"2025121302344994000_46.4.553.42","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S0026-895X(25)08704-8","article-title":"Epitope mapping studies with human anti-cytochrome P450 3A antibodies.","volume":"49","author":"Leeder","year":"1996","journal-title":"Mol Pharmacol"},{"key":"2025121302344994000_46.4.553.43","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1172\/JCI116843","article-title":"Two different cytochrome P450 enzymes are the adrenal antigens in autoimmune polyendocrine syndrome type I and Addison's disease.","volume":"92","author":"Winqvist","year":"1993","journal-title":"J Clin Invest"},{"key":"2025121302344994000_46.4.553.44","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)91829-W"},{"key":"2025121302344994000_46.4.553.45","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)91894-E"},{"key":"2025121302344994000_46.4.553.46","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(05)80258-2"},{"key":"2025121302344994000_46.4.553.47","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/0016-5085(94)90426-X","article-title":"Primary and secondary liver\/kidney microsomal autoantibody response following infection with hepatitis C virus.","volume":"106","author":"Mackie","year":"1994","journal-title":"Gastroenterology"},{"key":"2025121302344994000_46.4.553.48","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1365-2249.1991.tb08164.x","article-title":"Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis.","volume":"84","author":"Lohr","year":"1991","journal-title":"Clin Exp Immunol"},{"key":"2025121302344994000_46.4.553.49","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510240619"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.46.4.553","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T10:35:02Z","timestamp":1765622102000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.46.4.553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,4,1]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2000,4,1]]},"published-print":{"date-parts":[[2000,4,1]]}},"alternative-id":["10.1136\/gut.46.4.553"],"URL":"https:\/\/doi.org\/10.1136\/gut.46.4.553","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,4,1]]}}}