Ethanol‐induced inhibition of leukotriene degradation by ω‐oxidation

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Abstract
ω‐Oxidation of leukotrienes is a major pathway in the degradation and inactivation of these proinflammatory mediators. Ethanol inhibited this process in vivo and in vitro. In rat liver in vivo the catabolism of LTE4 to ω‐carboxylated leukotrienes was inhibited by 57% by an ethanol dose of 25 mmol/kg body mass administered intragastrically. The site of inhibition was the oxidation of ω‐hydroxy‐N‐acetyl‐LTE4 to ω‐carboxy‐N‐acetyl‐LTE4 resulting in an accumulation of ω‐hydroxy‐LTE4 and of N‐acetyl‐LTE4. Analogous results were obtained for the oxidative degradation of LTB4 and ω‐hydroxy‐LTB4 in rat hepatocyte suspensions. Ethanol, at a concentration of 12.5 mmol/l (0.07%; by vol.), caused 68% inhibition of the oxidation of ω‐hydroxy‐LTB4 leading to an accumulation of the biologically active LTB4 as well as of ω‐hydroxy‐LTB4. 4‐Methylpyrazole, an inhibitor of cytosolic alcohol dehydrogenase, at a concentration of 23 μmol/l inhibited the oxidation of ω‐hydroxy‐LTB4 by 50% in hepatocyte suspensions. The conversion of ω‐hydroxy‐LTB4 to ω‐carboxy‐LTB4 by rat and human liver cytosol was inhibited by ethanol with half maximal concentrations of 100 μmol/l and 300 μmol/l, respectively. Our measurements indicate that direct interference by ethanol of the ω‐oxidation of leukotrienes as well as an increased NADH/NAD+ ratio induced by ethanol led to the inhibition of leukotriene degradation. The impairment of leukotriene inactivation in the liver by ethanol may contribute to the development of the inflammatory reaction in acute alcoholic liver disease.

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