Maintenance of hepatic glutathione homeostasis and prevention of acetaminophen-induced cataract in mice by L-cysteine prodrugs.
Administration of acetaminophen (ACP, 3.0 mmol/kg, i.p.) to beta-naphthoflavone-induced C57 BL/6 mice led to the formation of bilateral cataracts within 8 hr with a 71% incidence. The hepatic glutathione (GSH) levels were reduced 99% and lenticular GSH levels reduced 42% in cataractous mice. Cataract formation was completely prevented by the co-administration of the L-cysteine prodrugs 2(R, S)-methylthiazolidine-4(R)-carboxylic acid (MTCA) and 2(R, S)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA) in two divided i.p. doses totaling 4.5 mmol/kg. 2-Oxo-L-thiazolidine-4-carboxylic acid (OTCA) was nearly equipotent, yielding only one cataract in 16 mice, but D-ribose-L-cysteine (RibCys, 5/16) and N-acetyl-L-cysteine (NAC, 9/14) were much less effective. Hepatic and lenticular GSH were maintained at near normal levels by MTCA, PTCA and OTCA. These results suggest that maintenance of adequate cellular GSH levels in the presence of ACP protects against cataract induction.
Rathbun
W B
WB
Department of Ophthalmology, University of Minnesota, Minneapolis, USA.
Killen
C E
CE
Holleschau
A M
AM
Nagasawa
H T
HT
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002386:Cataract / Q000139:chemically induced / Q000517:prevention & control*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011355:Prodrugs / Q000494:pharmacology*
D011355:Prodrugs; D000082:Acetaminophen; D005978:Glutathione; D003545:Cysteine