Does CYP4F2 inactivate leukotriene B4, and does rs2108622 T-carrier status reduce its activity?

The CYP4F2 enzyme plays a vital role in resolving inflammation by metabolizing leukotriene B4 (LTB4), but its clearance capacity is highly sensitive to genetic variations that alter its structural stability.

Metabolic pathway of LTB4 inactivation

• Direct oxidation: CYP4F2 acts as a primary hepatic LTB4 $\omega$-hydroxylase, converting the highly active inflammatory mediator LTB4 into 20-hydroxy-LTB4. This metabolite is subsequently oxidized to inactive 20-oxo-LTB4 and 20-carboxy-LTB4 to facilitate rapid systemic clearance.
• Hepatic clearance kinetics: Although CYP4F2 has a lower affinity for LTB4 (apparent $K_m$ of 45–75 µM) compared to the sub-micromolar affinity of the neutrophil-specific isoform CYP4F3A, its high expression density in human liver microsomes makes it the primary driver of systemic LTB4 clearance.

Mechanistic impact of rs2108622

• Structural destabilization: The rs2108622 (c.1297G>A) polymorphism results in a valine-to-methionine substitution at position 433 (V433M). This substitution reduces protein compactness, leading to accelerated post-translational degradation of the holoenzyme without affecting mRNA expression.
• Enzymatic impairment: Because of this accelerated degradation, T-allele carriers (CT or TT genotypes) exhibit a 40% to 60% reduction in specific activity ($V_{max}$) for key metabolic substrates, including 20-HETE and vitamin K1, while substrate affinity ($K_m$) remains unaltered. Clinically, this loss of function impairs vitamin K1 clearance, requiring higher maintenance doses of warfarin.

Bottom line

• Key takeaway: The scientific evidence supports the claim: CYP4F2 directly inactivates pro-inflammatory LTB4 through $\omega$-hydroxylation, and the rs2108622 T allele (V433M variant) structurally destabilizes the enzyme, resulting in a 40% to 60% reduction in overall catalytic activity.