Leukotriene B4 ω-side chain hydroxylation by CYP4F5 and CYP4F6

Leukotriene B4 (LTB4) is a lipid mediator that plays an important role in inflammation. Metabolism of LTB4 by cytochrome P450 (CYP) enzymes belonging to the CYP4F subfamily is considered to be of importance for the regulation of inflammation. This study investigates LTB4 metabolism by recombinant rat CYP4F5 and CYP4F6 expressed in a yeast system and by microsomes isolated from rat organs expressing CYP4F mRNA. CYP4F6 was found to convert LTB4 into 19-hydoxy- and 18-hydroxy-LTB4 with an apparent Km of 26 μM, and CYP4F5 was found to convert LTB4 primarily into 18-hydroxy-LTB4 with an apparent Km of 9.7 μM. The rate of formation of 18-hydroxy-LTB4 by CYP4F5 was surprisingly high. At a substrate concentration of 30 μM, the rate of formation was about 15 nmol/min/mg microsomal protein, approximately 30 times faster than the reaction catalyzed by CYP4F6. Analysis of LTB4 metabolism by microsomes isolated from various tissues from the rat suggests that CYP4F5 and CYP4F6 are active in the lung and to some extent in the brain, kidney, and testis. CYP4F5 and CYP4F6, due to their capacities to metabolize LTB4, may play important roles in modulating inflammatory response in these organs.