Inhibition of oxidative metabolism of tocopherols with ω- 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 α-tocopherol. It is well known that a commonly ingested form of vitamin E, γ-tocopherol, has greatly reduced plasma half-life (faster clearance) than α-tocopherol. The tocotrienols are metabolized even faster than γ-tocopherol. Both γ-tocopherol and α- and δ-tocotrienol possess intriguing biological activities that are different from α-tocopherol, making them potentially of interest for therapeutic use. Unfortunately, the fast clearance of non-α-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 α-tocopherol that act as inhibitors of Cyp4F2, the key monooxygenase responsible for ω-hydroxylation of the side chain of tocols. In particular, an ω-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 γ-CEHC production from γ-tocopherol of ∼1 nM when tested in HepG2 cells in culture. Furthermore, feeding of 1 to mice along with rapidly metabolized δ-tocopherol, resulted in a doubling of the δ-tocopherol/α-tocopherol ratio in liver ( P < 0.05). Thus, 1 may be a useful adjuvant to the therapeutic use of non-α-tocopherols.