Ethanol-induced inhibition of leukotriene degradation by omega-oxidation.
omega-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 omega-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 omega-hydroxy-N-acetyl-LTE4 to omega-carboxy-N-acetyl-LTE4 resulting in an accumulation of omega-hydroxy-N-acetyl-LTE4 and of N-acetyl-LTE4. Analogous results were obtained for the oxidative degradation of LTB4 and omega-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 omega-hydroxy-LTB4 by 50% in hepatocyte suspensions. The conversion of omega-hydroxy-LTB4 to omega-carboxy-LTB4 by rat and human liver cytosol was inhibited by ethanol with half maximal concentrations of 100 mumols/l and 300 mumols/l, respectively. Our measurements indicate that direct interference by ethanol of the omega-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.
Baumert
T
T
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Federal Republic of Germany.
Huber
M
M
Mayer
D
D
Keppler
D
D
D000818:Animals; D002458:Cell Fractionation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D015289:Leukotrienes; D007975:Leukotriene B4; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072470:Cytochrome P450 Family 4; C040780:leukotriene B4 20-hydroxylase