Evidence for leukotriene A4 as an intermediate in the conversion of 5-HPETE to leukotriene B4 catalyzed by cytochrome P-450.
Hydrolysis of 5-hydroperoxyeicosatetraenoic acid catalyzed by cytochrome P-450 in the absence of NADPH formed a product with spectral and HPLC characteristics identical with those of leukotriene B4, 5(S),12(R)-dihydroxy-6-cis,8,10-trans,14-cis-eicosatetraenoic acid (LTB4). The product mixture suggests that trans-5,6-oxido-7,9-trans,11,14-cis-eicosatetraenoic acid, leukotriene A4 (LTA4) is an intermediate in the reaction. We suggest that the formation of LTB4 with the essential 6-cis stereochemistry is due to tight binding of the 5-HPETE to the cytochrome P-450 at a site that does not allow it to isomerize to the kinetically favored 6,8,10-trans configuration during attack of hydroxyl ion at C-12.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D007536:Isomerism; D007700:Kinetics; D017572:Leukotriene A4; D007975:Leukotriene B4 / Q000096:biosynthesis*; D015289:Leukotrienes; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011817:Rabbits
D001095:Arachidonic Acids; D017572:Leukotriene A4; D015289:Leukotrienes; D007975:Leukotriene B4; C025348:arachidonic acid 5-hydroperoxide; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital