The objective of this study was to investigate the initial catabolic step of vitamin E and K metabolism, the ω-hydroxylation by human cytochrome P450 4F2 (CYP4F2).Methods and results:
Tocopherol (T) metabolism was compared using rat liver slices incubated with deuterated (d6)-RRR-α-T (d6-α-T), racemic 2S-α-T (2S, 4′RS, 8′RS α-T, 2S-α-T), or d2-γ-T (d2-γ-T). Following comparable uptake of each T by liver slices, twice as much 13′-OH-T was produced from 2S-α-T or d2-γ-T (39 ± 15 or 42 ± 5 pmol/g liver, respectively) as from d6-α-T (17 ± 2, p < 0.01). Kinetic studies were conducted using insect microsomes expressing human CYP4F2 incubated with d4-phylloquinone (d4-PK), d6-RRR-α-T, d3-SRR-α-T, or d2-γ-T. CYP4F2 demonstrated similar apparent maximal velocities (Vmax) when either of the α-Ts were used as substrates, which were less than the apparent d4-PK Vmax (p < 0.0002), while the CYP4F2 catalytic efficiency toward d4-PK (15.8 Vmax/Km) was five times greater than for α-Ts. Vitamin K had no effect on vitamin E catabolism, while vitamin E slightly decreased the d4-PK Vmax.Conclusion:
CYP4F2 discriminates between Ts and PK in vitro, but α-T does not apparently increase PK ω-hydroxylation by this mechanism.