ω-Hydroxylation of phylloquinone by CYP4F2 is not increased by α-tocopherol

Scope 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.