Hypoxia and CCl4-induced liver injury, but not acidosis, impair metabolism of cysteinyl leukotrienes in perfused rat liver.
Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."
Wettstein
M
M
Department of Internal Medicine, University of Freiburg, Federal Republic of Germany.
Gerok
W
W
Häussinger
D
D
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D017999:Leukotriene E4; D015289:Leukotrienes / Q000378:metabolism*; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000031:analogs & derivatives / Q000378:metabolism
D015289:Leukotrienes; D013189:SRS-A; D017999:Leukotriene E4; D002251:Carbon Tetrachloride