Inhibition of leukotriene omega-oxidation by omega-trifluoro analogs of leukotrienes.
omega-Oxidation with subsequent beta-oxidation from the omega-end is the major pathway for inactivation and degradation of leukotrienes. Oxidative degradation of leukotriene E4 (LTE4), N-acetyl-LTE4, and LTB4 was inhibited by the omega-trifluoro analogs of LTE4, omega-trifluoro-LTE4 (omega-F3-LTE4), and (1S,2R)-5-(3-[1-hydroxy-15,15,15-trifluoro-2-(2-1H- tetrazol-5-ylethyl-thio)pentadeca-3(E),5(Z)-dienyl+ ++]phenyl)-1H-tetrazole (LY 245769). The latter substance inhibited the oxidative degradation of LTE4 and N-acetyl-LTE4 in the rat in vivo by 50% at a dose of 7 mumol/kg body weight. In rat hepatocyte cultures both omega-trifluoro analogs interfered with the omega-oxidation of N-acetyl-LTE4 and LTB4 with IC50 values of about 4 microM. Both analogs inhibited the omega-hydroxylation in isolated rat liver microsomes with IC50 values between 16 and 37 microM. This inhibition is apparently competitive. In addition, in liver cytosol, the conversion of the omega-hydroxylated leukotrienes to omega-carboxy-LTE4 and omega-carboxy-LTB4 was inhibited by both compounds. omega-Trifluoro analogs of leukotrienes provide a new tool for interfering with the inactivation of leukotrienes in the omega-oxidation pathway.
Jedlitschky
G
G
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
Leier
I
I
Huber
M
M
Mayer
D
D
Keppler
D
D
D000818:Animals; D001646:Bile / Q000737:chemistry; D002478:Cells, Cultured; D007975:Leukotriene B4 / Q000378:metabolism*; D017999:Leukotriene E4; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*
D013189:SRS-A; D013440:Sulfides; D013777:Tetrazoles; C066222:LY 245769; C066221:20,20,20-trifluoroleukotriene E4; D007975:Leukotriene B4; D017999:Leukotriene E4