{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T10:15:35Z","timestamp":1781345735091,"version":"3.54.1"},"reference-count":12,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2006,1,12]],"date-time":"2006-01-12T00:00:00Z","timestamp":1137024000000},"content-version":"vor","delay-in-days":407,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of the New York Academy of Sciences"],"published-print":{"date-parts":[[2004,12]]},"abstract":"<jats:p><jats:bold>A<jats:sc>bstract<\/jats:sc>: <\/jats:bold> Tocopherols are known to undergo metabolism to phytyl chain\u2010shortened metabolites excreted in urine. We sought to characterize the pathway, including associated enzymes, involved in this biotransformation. We previously found that human hepatoblastoma (HepG2) cultures metabolized tocopherols to their corresponding short\u2010chain carboxychromanols. Putative metabolites of \u03b3\u2010tocopherol that contained intact chromanol moieties were structurally identified using HepG2 cultures and electron impact gas chromatography\u2010mass spectrometry. A microsomal assay for synthesis of the initial \u03c9\u2010oxidation metabolites was developed and used to screen several recombinant human liver cytochrome P450 isozymes for \u03c9\u2010hydroxylase activity. Seven metabolites of \u03b3\u2010tocopherol were identified in HepG2 cultures, including 13\u2032\u2010hydroxy\u2010\u03b3\u2010TOH and all six carboxychromanols predicted by sequential \u03c9\u2010oxidation truncation. Rat and human liver microsomes catalyzed synthesis of 13\u2032\u2010OH\u2010 and 13\u2032\u2010COOH\u2010\u03b3\u2010TOH, but not other metabolites, in the presence of NADPH. Inclusion of NAD favored synthesis of the 13\u2032\u2010COOH metabolite. Recombinant CYP4F2, but not other major human liver CYP isoforms (including CYP3A4 and 3A7), exhibited tocopherol\u2010\u03c9\u2010hydroxylase activity. Liver microsomes and recombinant CYP4F2 both exhibited substrate preference for \u03b3\u2010TOH over \u03b1\u2010TOH, and recent studies show that tocotrienols are catabolized more extensively than the corresponding tocopherols. Comparative rates of \u03c9\u2010oxidation of tocochromanols in hepatocytes are inversely related to biopotency and directly related to cytotoxicity of these substances in macrophages. The liver contains a cytochrome P450\u2010mediated pathway that preferentially catabolizes \u201cnon\u2010\u03b1\u201d tocochromanols to excretable metabolites. This metabolic pathway appears central to the optimization of tissue tocochromanol status.<\/jats:p>","DOI":"10.1196\/annals.1331.002","type":"journal-article","created":{"date-parts":[[2005,3,7]],"date-time":"2005-03-07T19:07:39Z","timestamp":1110222459000},"page":"13-21","source":"Crossref","is-referenced-by-count":51,"title":["Discovery, Characterization, and Significance of the Cytochrome P450 \u03c9\u2010Hydroxylase Pathway of Vitamin E Catabolism"],"prefix":"10.1111","volume":"1031","author":[{"given":"ROBERT S.","family":"PARKER","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"TIMOTHY J.","family":"SONTAG","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JOY E.","family":"SWANSON","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CHARLES C.","family":"McCORMICK","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,1,12]]},"reference":[{"key":"e_1_2_9_2_2","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/S0022-2275(20)32145-3","article-title":"Measurement of the 2,7,8\u2010trimethyl\u20102\u2010(\u03b2\u2010carboxyethyl)\u20106\u2010hydroxychroman metabolite of \u03b3\u2010tocopherol in human urine: evidence for urinary excretion as a major route of elimination of \u03b3\u2010tocopherol","volume":"40","author":"Swanson J.","year":"1999","journal-title":"J. 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