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* Departments of Biochemistry, Queen's University, Kingston, ON, K7L 3N6, Canada
Pathology, Queen's University, Kingston, ON, K7L 3N6, Canada
Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada
1 To whom correspondence should be addressed. e-mail: gj1{at}post.queensu.ca
Two mammalian hCYP26A expression systems have been used to analyze the metabolic products of CYP26A. Through the use of extensive HPLC, UV spectroscopy, and liquid chromatography/tandem mass spectrometry (LC-MS/MS) methodology, we have conclusively demonstrated that the complex mixture of products comprises 4-OH-all-trans-retinoic acid, 4-oxo-all-trans-retinoic acid, and 18-OH-all-trans-retinoic acid, and more polar products, partially identified as dihydroxy and mono-oxo, mono-hydroxy derivatives. These more polar products are presumed to result from multiple hydroxylations on the ß-ionone ring. The inter-relationship of initial and polar metabolites was inferred from both gene-dose and time-course experiments.
Both initial and secondary metabolic steps after 4-oxo-all-trans-retinoic acid are ketoconazole-sensitive, suggesting that steps in the production of water-soluble metabolites are cytochrome P450-dependent.
Abbreviations: atRA, all-trans-retinoic acid; ddH2O, deionized distilled water; ddH2O/A/GAA, ddH2O-acetonitrile-glacial acetic acid; DIA, daughter ion analysis; DPPD, 1,2-Dianilinoethane (N,N'- diphenylethylene-diamine); H/I/M/GAA, hexane-isopropanol-methanol-glacial acetic acid; MS, mass spectrometry; TIC, total ion current
Supplementary key words vitamin A metabolism • retinoids • cytochrome P450 • RAI-1
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