Bylund Johan, Harder Adam G, Maier Kristopher G, Roman Richard J, Harder David R
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Arch Biochem Biophys. 2003 Apr 1;412(1):34-41. doi: 10.1016/s0003-9861(03)00030-4.
Leukotriene B(4) (LTB(4)) is a lipid mediator that plays an important role in inflammation. Metabolism of LTB(4) by cytochrome P450 (CYP) enzymes belonging to the CYP4F subfamily is considered to be of importance for the regulation of inflammation. This study investigates LTB(4) 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 LTB(4) into 19-hydoxy- and 18-hydroxy-LTB(4) with an apparent K(m) of 26 microM, and CYP4F5 was found to convert LTB(4) primarily into 18-hydroxy-LTB(4) with an apparent K(m) of 9.7 microM. The rate of formation of 18-hydroxy-LTB(4) by CYP4F5 was surprisingly high. At a substrate concentration of 30 microM, the rate of formation was about 15 nmol/min/mg microsomal protein, approximately 30 times faster than the reaction catalyzed by CYP4F6. Analysis of LTB(4) 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 LTB(4), may play important roles in modulating inflammatory response in these organs.
白三烯B(4)（LTB(4)）是一种脂质介质，在炎症中起重要作用。属于CYP4F亚家族的细胞色素P450（CYP）酶对LTB(4)的代谢被认为对炎症调节具有重要意义。本研究调查了在酵母系统中表达的重组大鼠CYP4F5和CYP4F6以及从表达CYP4F mRNA的大鼠器官分离的微粒体对LTB(4)的代谢情况。发现CYP4F6将LTB(4)转化为19-羟基-LTB(4)和18-羟基-LTB(4)，表观K(m)为26 microM，并且发现CYP4F5主要将LTB(4)转化为18-羟基-LTB(4)，表观K(m)为9.7 microM。CYP4F5形成18-羟基-LTB(4)的速率惊人地高。在底物浓度为30 microM时，形成速率约为15 nmol/min/mg微粒体蛋白，比CYP4F6催化的反应快约30倍。对从大鼠各种组织分离的微粒体对LTB(4)代谢的分析表明，CYP4F5和CYP4F6在肺中具有活性，在大脑、肾脏和睾丸中也有一定程度的活性。由于其代谢LTB(4)的能力，CYP4F5和CYP4F6可能在调节这些器官的炎症反应中起重要作用。
