{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T17:22:32Z","timestamp":1760980952900},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2005,9,9]],"date-time":"2005-09-09T00:00:00Z","timestamp":1126224000000},"content-version":"vor","delay-in-days":5365,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratog Carcinog Mutagen"],"published-print":{"date-parts":[[1991,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>It has been reported that fractionated doses of 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg\/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 \u00d7 100 mg\/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and\/or its metabolites. The major plasma metabolite of 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoic acid in the mouse was 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoyl\u2010\u03b2\u2010glucuronide, followed by the 4\u2010oxo metabolites and all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid. Transfer to the mouse embryo was very efficient for all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid, whereas, it was tenfold less efficient for 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoic acid and 100\u2010fold less efficient for 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoyl\u2010\u03b2\u2010glucuronide. The isomer all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid was found in the placenta at concentrations two\u2010 to three\u2010fold higher than in the plasma, suggesting placental accumulation as well as placental <jats:italic>cis\/trans<\/jats:italic> isomerization. Since 13\u2010<jats:italic>cis<\/jats:italic>\u2010retinoyl\u2010\u03b2\u2010glucuronide and 13\u2010<jats:italic>cis<\/jats:italic>\u2010 and all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid, a well\u2010known potent teratogen detected at concentrations of between 590 and 80 ng\/g for 10 critical hours during gestation, could have been the major component.<\/jats:p>","DOI":"10.1002\/tcm.1770110104","type":"journal-article","created":{"date-parts":[[2006,2,4]],"date-time":"2006-02-04T12:47:41Z","timestamp":1139057261000},"page":"21-30","source":"Crossref","is-referenced-by-count":33,"title":["Isotretinoin (13\u2010<i>cis<\/i>\u2010retinoic acid) metabolism, <i>cis<\/i>\u2010<i>trans<\/i> isomerization, glucuronidation, and transfer to the mouse embryo: Consequences for teratogenicity"],"prefix":"10.1002","volume":"11","author":[{"given":"J. Creech","family":"Kraft","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chr.","family":"Eckhoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. M.","family":"Kochhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G.","family":"Bochert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I.","family":"Chahoud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H.","family":"Nau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,9,9]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(83)90538-X"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420330315"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(84)92866-6"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198510033131401"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/tcm.1770040407"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420360110"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(87)90253-5"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(89)90099-9"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/01483918808069040"},{"key":"e_1_2_1_11_2","unstructured":"Creech KraftJ BailyJR RobertsLG FischerB WittfohtW NauH SlikkerWJr: Distribution and metabolism of 13\u2010cisand all\u2010trans\u2010retinoic acid in the plasma of cynomolgus monkeys and the identification of the conjugate metabolites 13\u2010cisand all\u2010trans\u2010retinoyl\u2010\u03b2\u2010glucuronide: A comparison to one human case study with 13\u2010cis\u2010retinoic acid.Drug Metab Dispos1990(in press)."},{"key":"e_1_2_1_12_2","first-page":"123","volume-title":"Methods in Prenatal Toxicology","author":"Chahoud I","year":"1977"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.3109\/10520292609115636"},{"key":"e_1_2_1_14_2","doi-asserted-by":"crossref","unstructured":"EckhoffC SlikkerWJr WittfohtW NauH: Characterization of oxidized and glucuronidated metabolites of retinol in monkey plasma by thermospray liquid chromatography\/mass spectometry.Biomed Mass Spectrom1990(in press).","DOI":"10.1002\/bms.1200190708"},{"key":"e_1_2_1_15_2","first-page":"400","article-title":"Retinoyl\u2010\u03b2\u2010glucuronide is not teratogenic in rats","volume":"3","author":"Gunning DB","year":"1988","journal-title":"FASEB J"},{"key":"e_1_2_1_16_2","doi-asserted-by":"publisher","DOI":"10.3109\/03602538409033562"},{"key":"e_1_2_1_17_2","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1016\/S0021-9258(18)34812-9","article-title":"Metabolites of all\u2010trans\u2010retinoic acid in bile; identification of all\u2010trans\u2010 and 13\u2010cis\u2010retinoyl\u2010\u03b2\u2010glucuronides","volume":"257","author":"Zile MH","year":"1982","journal-title":"J Biol Chem"},{"key":"e_1_2_1_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(81)90180-5"},{"key":"e_1_2_1_19_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1093\/ajcn\/43.4.481","article-title":"Retinoyl\u2010\u03b2\u2010glucuronide: An endogenous compound of human blood","volume":"43","author":"Barua AB","year":"1986","journal-title":"Am J Clin Nutr"},{"key":"e_1_2_1_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(88)90003-8"},{"key":"e_1_2_1_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4274(89)90172-0"},{"key":"e_1_2_1_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/296564a0"},{"key":"e_1_2_1_23_2","first-page":"269","article-title":"The effects of local application of retinoic acid to the anterior margin of the developing chick limb","volume":"78","author":"Summerbell D","year":"1983","journal-title":"J. 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