{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:53:13Z","timestamp":1783075993163,"version":"3.54.6"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":2130,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2003,4]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>The aim of the present study was to identify human cytochrome <jats:italic>P<\/jats:italic>\u2010450 isoforms (CYPs) involved in 5\u2010sulphoxidation and N\u2010demethylation of the simplest phenothiazine neuroleptic promazine in human liver.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The experiments were performed in the following <jats:italic>in vitro<\/jats:italic> models: (A) a study of promazine metabolism in liver microsomes\u2014(a) correlations between the rate of promazine metabolism and the level and activity of CYPs; (b) the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2\u2014furafylline, CYP2D6\u2014quinidine, CYP2A6+CYP2E1\u2014diethyldithiocarbamic acid, CYP2C9\u2014sulfaphenazole, CYP2C19\u2014ticlopidine, CYP3A4\u2014ketoconazole); (B) promazine biotransformation by cDNA\u2010expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C) promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicin\u2014CYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8\u2010tetrachlordibenzeno\u2010<jats:italic>p<\/jats:italic>\u2010dioxin (TCDD)\u2014CYP1A1\/1A2 inducer).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In human liver microsomes, the formation of promazine 5\u2010sulphoxide and <jats:italic>N<\/jats:italic>\u2010desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin <jats:italic>O<\/jats:italic>\u2010deethylase and acetanilide 4\u2010hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N\u2010desmethylpromazine was correlated well with <jats:italic>S<\/jats:italic>\u2010mephenytoin 4\u2032\u2010hydroxylation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5\u2010sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine <jats:italic>N<\/jats:italic>\u2010demethylation in human liver microsomes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The cDNA\u2010expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) was as follows: 1A1&gt;2B6&gt;1A2&gt;2C9&gt;3A4&gt;2E1&gt;2A6&gt;2D6&gt;2C19 for 5\u2010sulphoxidation and 2C19&gt;2B6&gt;1A1&gt;1A2&gt;2D6&gt;3A4&gt;2C9&gt;2E1&gt;2A6 for N\u2010demethylation. The highest intrinsic clearance (<jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub>\/<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5\u2013 sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of <jats:italic>N<\/jats:italic>\u2010demethylation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5\u2010sulphoxide and <jats:italic>N<\/jats:italic>\u2010desmethylpromazine.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5\u2010sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse <jats:italic>N<\/jats:italic>\u2010demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5\u2010sulphoxidation and N\u2010demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2003) <jats:bold>138<\/jats:bold>, 1465\u20131474. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705195\">10.1038\/sj.bjp.0705195<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705195","type":"journal-article","created":{"date-parts":[[2003,4,29]],"date-time":"2003-04-29T17:18:42Z","timestamp":1051636722000},"page":"1465-1474","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Contribution of human cytochrome <i>P<\/i>\u2010450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine"],"prefix":"10.1111","volume":"138","author":[{"given":"Jacek","family":"W\u00f3jcikowski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydiane","family":"Pichard\u2010Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Maurel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W\u0142adys\u0142awa A","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498259509061859"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.3109\/00498259009046835"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(93)90272-X"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1991.77"},{"key":"e_1_2_7_6_1","first-page":"492","article-title":"Stereo\u2010 and regioselective N\u2010and S\u2010oxidation of tertiary amines and sulfides in the presence of adult human liver microsomes","volume":"21","author":"CASHMAN J.R.","year":"1993","journal-title":"Drug Metab. 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