title: Inhibition of oxidative metabolism of tocopherols with omega-N-heterocyclic derivatives of vitamin E.
abstract: The oxidative metabolism of tocopherols and tocotrienols by monooxygenases is a key factor in the plasma and tissue clearance of forms of vitamin E other than alpha-tocopherol. It is well known that a commonly ingested form of vitamin E, gamma-tocopherol, has greatly reduced plasma half-life (faster clearance) than alpha-tocopherol. The tocotrienols are metabolized even faster than gamma-tocopherol. Both gamma-tocopherol and alpha- and delta-tocotrienol possess intriguing biological activities that are different from alpha-tocopherol, making them potentially of interest for therapeutic use. Unfortunately, the fast clearance of non-alpha-tocopherols from animal tissues is a significant hurdle to maximizing their effect(s) as dietary supplements. We report here the design and synthesis of N-heterocycle-containing analogues of alpha-tocopherol that act as inhibitors of Cyp4F2, the key monooxygenase responsible for omega-hydroxylation of the side chain of tocols. In particular, an omega-imidazole containing compound, 1, [(R)-2-(9-(1H-imidazol-1-yl)nonyl)-2,5,7,8-tetramethylchroman-6-ol] had an ED(50) for inhibition of gamma-CEHC production from gamma-tocopherol of approximately 1 nM when tested in HepG2 cells in culture. Furthermore, feeding of 1 to mice along with rapidly metabolized delta-tocopherol, resulted in a doubling of the delta-tocopherol/alpha-tocopherol ratio in liver (P<0.05). Thus, 1 may be a useful adjuvant to the therapeutic use of non-alpha-tocopherols.
authors.affiliation: Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ont., Canada L2S 3A1.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ohnmacht
authors.forename: Phillip
authors.initials: P
authors.lastname: Nava
authors.forename: Ryan
authors.initials: R
authors.lastname: West
authors.forename: Robert
authors.initials: R
authors.lastname: Parker
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001646:Bile / Q000201:enzymology; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D024505:Tocopherols / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D024508:Tocotrienols / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives*
chemical_list: D001562:Benzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D024508:Tocotrienols; D014230:Triazoles; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C479073:tocopherol-omega-hydroxylase; D024505:Tocopherols