[The Heinrich-Wieland Prize presentation. Metabolism and analysis of leukotrienes in vivo]

Abstract

Leukotrienes are potent mediators of inflammatory and allergic reactions involved, among others, in endotoxin action and shock, tissue trauma, acute liver injury, hepatorenal syndrome, inflammatory bowel disease, acute pancreatitis, and asthma. Studies on metabolism and analysis of these arachidonate metabolites in vivo are a prerequisite for an improved understanding of their role under physiological and pathophysiological conditions and for the development of inhibitors of leukotriene synthesis and of receptor antagonists. Leukotriene C4 and its metabolites, collectively termed the cysteinyl leukotrienes, are predominantly inactivated by the liver. Rapid hepatocellular uptake is followed by partial metabolic inactivation, comprising omega-oxidation and N-acetylation of leukotriene E4, and excretion into bile. A minor portion of the cysteinyl leukotrienes undergoes enterohepatic circulation. In all species investigated so far, hepatobiliary elimination of cysteinyl leukotrienes predominates over renal excretion. Analysis of the systemic production of cysteinyl leukotrienes in vivo has been accomplished by radioimmunological determination of species-characteristic index metabolites in bile after their separation by high-performance liquid chromatography. The mercapturate N-acetyl-leukotriene E4 is the index metabolite of choice in the rat. In man, leukotriene E4 is the predominant endogenous cysteinyl leukotriene in both bile and urine. The amounts of cysteinyl leukotrienes detected under various pathophysiological conditions may be sufficient to induce known phenomena associated with the respective disease. As shown under experimental conditions, inhibition of leukotriene synthesis or receptor antagonism can serve as therapeutic approaches.