Metabolism and excretion of cysteinyl-leukotrienes

In vitro and in vivo experiments have demonstrated that a major pathway of metabolism of the glutathione containing leukotrienes involves modifications of the tripeptide substituent. The metabolic alterations are initiated by elimination of the N-terminal gamma-glutamyl residue, catalyzed by the enzyme gamma-glutamyl transferase. This reaction is followed by hydrolysis of the remaining peptide bond resulting in elimination of the C-terminal glycine residue. The enzyme catalyzing the latter reaction is a membrane bound dipeptidase which occurs in kidney and other tissues. The product formed by these reactions, leukotriene E4, has been tentatively identified as a urinary metabolite in man following intravenous administration of leukotriene C4. In rats, two major fecal metabolites of leukotriene C4 were characterized as having the structures N-acetyl leukotriene E4 and N-acetyl 11-trans leukotriene E4. These compounds are formed from leukotriene E4 and 11-trans leukotriene E4 in reactions with acetyl coenzyme A. A membrane bound enzyme, present in liver, kidney and other tissues, catalyzes these reactions.