Cysteine isopropylester protects against paracetamol-induced toxicity.
Cysteine isopropylester (CIPE), a novel ester of cysteine, has been synthesized in order to evaluate its potential as a chemoprotectant. The increased lipophilicity of the ester relative to cysteine should facilitate its entry into cells where, following hydrolysis, it should act as an intracellular source of cysteine or be utilized for the synthesis of glutathione so protecting the cell against various types of chemical insult. In this study, we evaluate the ability of CIPE to protect against paracetamol-induced hepatotoxicity in mice. When administered to mice, CIPE produced a rapid but transient elevation of levels of non-protein sulphydryls (NPSH) in liver, lung, kidney and spleen. The greatest increase in NPSH was seen in the lung, but after 60 min all NPSH values had returned to control levels, demonstrating the capacity of the mouse to rapidly metabolize both CIPE and cysteine. In mice pretreated with benzo(a)pyrene, CIPE protected against paracetamol-induced toxicity as measured by the prevention of mortality, the fall in hepatic NPSH and the decreased elevation of serum transaminases. CIPE (1.5 mmol/kg) appeared as effective as N-acetylcysteine (1.5 mmol/kg). Higher doses of CIPE (3.0 mmol/kg) alone were toxic to mice induced with benzo(a)pyrene but not to control or phenobarbitone-induced mice. The mechanism of this increased toxicity is unclear. CIPE has a short in vivo half life but was capable of protecting against paracetamol-induced toxicity. The potential of CIPE and other related cysteine esters to act as chemoprotectants merits further investigation.
Butterworth
M
M
Toxicology Unit, School of Pharmacy, University of London, U.K.
Upshall
D G
DG
Smith
L L
LL
Cohen
G M
GM
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001564:Benzo(a)pyrene / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism / Q000517:prevention & control*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D001564:Benzo(a)pyrene; D000082:Acetaminophen; C073222:cysteine isopropyl ester; D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine