2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity.
A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD90 doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl-, and 2(RS)-n- pentylthiazolidine -4(R)-carboxylic acids (compounds 1b,d,e, respectively) were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl-, and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c,f,g) were less protective. The enantiomer of 1b, viz., 2(RS)- methylthiazolidine -4(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase [Km = 1.1 x 10(-4) M; Vmax = 5.4 mumol min-1 (mg of protein)-1]. Compound 1b was not a substrate for proline oxidase but dissociated to L-cysteine in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D2O (k1 = 2.5 X 10(-5) s), suggesting that opening of the thiazolidine ring must have taken place. Indeed, 1b labeled with 14C in the 2 and methyl positions was rapidly metabolized by the rat to produce 14CO2, 80% of the dose being excreted in this form in the expired air after 24 h. It is suggested that these 2-substituted thiazolidine-4(R)-carboxylic acids are prodrugs of L-cysteine that liberate this sulfhydryl amino acid in vivo by nonenzymatic ring opening, followed by solvolysis.
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002250:Carbon Radioisotopes; D003545:Cysteine / Q000494:pharmacology*; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000201:enzymology; D011394:Proline Oxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D002250:Carbon Radioisotopes; D007202:Indicators and Reagents; D013844:Thiazoles; D000082:Acetaminophen; D011394:Proline Oxidase; D003545:Cysteine