Synthesis of beta-oxidation products as potential leukotriene metabolites and their detection in bile of anesthetized rat.
Two novel beta-oxidation products of peptido leukotrienes, 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetyl LTE4 and 18-carboxy-19,20-dinor-N-acetyl LTE4, were prepared by total synthesis and used to identify previously unknown polar rat biliary metabolites. When [3H] LTC4 and synthetic N-acetyl-LTE4 were administered intravenously to anesthetized inbred male rats, extraction of the bile and subsequent reverse-phase HPLC fractionation allowed the isolation of two novel metabolites of N-acetyl-LTE4. Comparison of U.V. spectra and coelution experiments revealed that these metabolites correspond to the above-mentioned synthetic beta-oxidation products. This was further confirmed by the coelution of the corresponding methyl esters. Oxidative ozonolysis of the metabolically produced 16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetyl LTE4 (major metabolite) confirmed the absence of the 14,15-unsaturation. The presence of these metabolites indicates that peptide leukotrienes undergo N-acetylation followed by omega and subsequent beta-oxidation in the anesthetized rat.
Delorme
D
D
Department of Medicinal Chemistry, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec.
Foster
A
A
Girard
Y
Y
Rokach
J
J
D000818:Animals; D001646:Bile / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives* / Q000378:metabolism
D015289:Leukotrienes; D013189:SRS-A; C058840:18-carboxy-19,20-dinor-N-acetylleukotriene E4; C058841:16-carboxy-17,18,19,20-tetranor-14,15-dihydro-N-acetylleukotriene E4