Inhibition of rat liver glutathione S-transferases by piriprost: kinetics of the inhibition and preliminary evidence that piriprost may be a poor alternative substrate for these enzymes.
The administration of tritiated piriprost, an inhibitor of leukotriene formation, to rats resulted in its rapid excretion. Some 90 percent of the initial dose was excreted in the feces and only five to six percent were recovered in the urine, regardless of the route of administration of the compound. The finding of significant, though low, residual activity in the liver even seven days after dosing (0.016 and 0.072% of dose in orally and iv-treated animals, respectively) suggested that piriprost may be bound by proteins in liver which play a role in detoxification. The finding that piriprost is a potent inhibitor of several partially purified cytosolic liver glutathione S-transferases ( EC 2.5.1.18) is consistent with this suspicion. Kinetic studies indicate that the inhibition may be competitive with the chromogenic substrate, chloro-2,4-dinitrobenzene (Ki 1-2 microM) and non-competitive with respect to glutathione when the second substrate was present at saturating concentration. Incubation of one to four micromolar radiolabeled tritiated piriprost with glutathione resulted in the gradual formation of a series of products which could be detected by high pressure liquid chromatography. The formation of these products was stimulated by the presence of glutathione S-transferase although the same products were also formed in the absence of the enzyme.
D000818:Animals; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology* / Q000031:analogs & derivatives; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors*; D014316:Tritium
D013189:SRS-A; D014316:Tritium; D011464:Epoprostenol; D005982:Glutathione Transferase; D005978:Glutathione; C035296:piriprost