Protection by L-2-oxothiazolidine-4-carboxylate, a cysteine prodrug, against 1,1-dichloroethylene hepatotoxicity in rats is associated with decreases in toxin metabolism and cytochrome P-450.
Our objective was to determine if the intracellular cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTZ), would protect rats against the hepatotoxicity of 1,1-dichloroethylene (DCE) by altering the toxin's biologic fate. Fasted male rats were pretreated with 10 mmol of OTZ per kg s.c. in saline or with saline only 1 hr before administration of 14C-labeled DCE (50 mg/kg) p.o. in mineral oil. Serial blood samples were taken from permanent jugular cannulas between 1 and 24 hr to monitor the time course of injury and circulating levels of 14C-derived label. DCE caused less liver injury in the OTZ-pretreated group. This protection was associated with about 50% less total, acid soluble and acid precipitable 14C-label in serum; 30% less label in urine; and at 24 hr, 30 to 68% less covalently bound label in liver, kidney and lung. Extent of peak liver injury in individual animals correlated well with the amount of 14C-label in serum at early times and with the amount covalently bound to liver at 24 hr, but correlated poorly with label excreted into urine. An explanation for the apparent decrease in DCE metabolism by OTZ-pretreated animals was investigated by examining effects of OTZ on liver constituents known to have a role in DCE metabolism. Fasted rats given 10 mmol of OTZ per kg showed a persistent loss of hepatic cytochrome P-450 at 3 and 6 hr whereas their hepatic and renal reduced glutathione contents were transiently diminished at 3 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Moslen
M T
MT
Department of Pathology, University of Texas Medical Branch, Galveston.
Whitehead
R F
RF
Ferguson
A E
AE
Kanz
M F
MF
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004000:Dichloroethylenes / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000032:analysis; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D011761:Pyrrolidonecarboxylic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
D004000:Dichloroethylenes; D006843:Hydrocarbons, Chlorinated; D013844:Thiazoles; D053778:Thiazolidines; C029297:vinylidene chloride; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid