Failure of glutathione and cysteine prodrugs to block the chlorpropamide-induced inhibition of aldehyde dehydrogenase in vivo.
Augmentation of cellular L-cysteine or glutathione (GSH) levels in vivo by the administration of prodrugs of L-cysteine or GSH, viz. 2(R,S)-methylthiazolidine-4(R)-carboxylic acid (MTCA), 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-car boxylic acid (RibCys) and GSH monoethyl ester (GSH-OEt), did not block the inhibition of aldehyde dehydrogenase (AlDH) by chlorpropamide (CP) or N1-ethylchlorpropamide (N1-EtCP), as shown by their inability to protect AlDH and thereby prevent the elevation of blood acetaldehyde (AcH) in ethanol-treated rats. Since the formation of an alkylcarbamoylating species by conjugation of n-propylisocyanate, a potential metabolite of CP or N1-EtCP, with GSH or L-cysteine is possible, intervention by GSH or cysteine may not produce a detoxified product. Evaluation of the two products that could theoretically be produced in vivo, viz. S-(n-propylcarbamoyl)-L-cysteine and S-(n-propylcarbamoyl)-GSH, indicated that these compounds inhibit rather than spare AlDH in rats. Indeed, the latter were as effective as N1-EtCP, a direct acting inhibitor of AlDH, and all three were better inhibitors of AlDH in vivo than CP itself. Thus, formation of S-conjugates of the active CP metabolite produced in vivo may not be a detoxication process, but may in fact represent redistribution of a transportable form of this highly reactive metabolite.
Shirota
F N
FN
Medical Research Laboratories, Veterans Affairs Medical Center, Minneapolis, MN 55417.
Elberling
J A
JA
Nagasawa
H T
HT
DeMaster
E G
EG
D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D002747:Chlorpropamide / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology* / Q000031:analogs & derivatives; D000431:Ethanol / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines
D011355:Prodrugs; D013844:Thiazoles; D053778:Thiazolidines; C057478:N(1)-ethylchlorpropamide; C070066:2-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4-carboxylic acid; D000431:Ethanol; C008499:2-methylthiazolidine-4-carboxylic acid; C042431:S-ethyl glutathione; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; D000079:Acetaldehyde; D003545:Cysteine; D002747:Chlorpropamide