Inhibition of leukotriene D4 catabolism by D-penicillamine.
Inhibition of the catabolism of the most biologically potent cysteinyl leukotriene, LTD4, was studied in rat hepatoma cells in vitro and in the rat in vivo. LTD4 dipeptidase, an ectoenzyme on the surface of AS-30D hepatoma cells, exhibited an apparent Km value of 6.6 microM for LTD4. D-Penicillamine and L-penicillamine inhibited this enzyme activity with apparent Ki values of 0.46 mM and 0.21 mM respectively. Bestatin, an inhibitor of the aminopeptidase activity of hepatoma cells, did not affect LTD4 hydrolysis at concentrations as high as 5 mM, indicating that the aminopeptidase did not contribute to LTD4 catabolism. In the rat in vivo, D-penicillamine also inhibited LTD4 catabolism. After intravenous injection of [3H]LTC4 an accumulation of [3H]LTD4 and a retarded formation of [3H]LTE4 were observed in the circulating blood after D-penicillamine pretreatment. Within 1 h after intravenous [3H]LTC4 injection, about 80% of the administered radioactivity was recovered in bile. After D-penicillamine pretreatment [3H]LTD4 was the major biliary leukotriene metabolite, whereas in untreated controls leukotriene metabolites more polar than LTC4 predominated in bile. After stimulation of endogenous leukotriene production in vivo by platelet-activating factor, N-acetyl-LTE4 was the major cysteinyl leukotriene detected in bile. D-Penicillamine treatment prior to platelet-activating factor resulted in the accumulation of LTD4, which under these circumstances was the major endogenous leukotriene metabolite detected in bile.
D000818:Animals; D001646:Bile / Q000378:metabolism; D004150:Dipeptidases / Q000037:antagonists & inhibitors; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D010396:Penicillamine / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D013189:SRS-A / Q000378:metabolism*
D010972:Platelet Activating Factor; D013189:SRS-A; D004150:Dipeptidases; C036942:leukotriene D4 dipeptidase; D010396:Penicillamine