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N-acetylcysteine is the drug of choice for the treatment of acetaminophen poisoning, yet the mechanism of protection in vivo is unknown. Prevention of liver injury could result from decreased production of the toxic intermediate(s), from increased capacity to detoxify the toxic intermediate(s) or from increased ability of the tissue to withstand or even repair the molecular damage caused by the toxic species. Treatment of mice with N-acetylcysteine (1200 mg/kg p.o.) was found to prevent the hepatic damage caused by 1000 mg/kg p.o. of acetaminophen. Possible mechanisms for this hepatoprotective effect were examined by measurement at different time points of acetaminophen and its metabolites in plasma, urine, bile and whole-body homogenates and by evaluation of the changes in these parameters caused by treatment with N-acetylcysteine. A high-pressure liquid chromatographic method was developed to measure the majority urinary metabolites of acetaminophen and was validated by desorption chemical ionization mass spectral analysis of individual metabolites. Minimal differences in the concentration of unchanged acetaminophen and metabolites in whole-body homogenates at 4, 6 and 24 hr postdose were noted for N-acetylcysteine-treated vs. vehicle-treated mice. These results are incompatible with a decreased formation of the toxic species secondary to delayed acetaminophen absorption from the gastrointestinal tract or with an increased clearance of acetaminophen via nontoxic pathways such as sulfation as plausible mechanisms for the observed hepatoprotection.(ABSTRACT TRUNCATED AT 250 WORDS)
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
March 1985,
The Journal of pharmacology and experimental therapeutics,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
February 1986,
The Journal of pharmacology and experimental therapeutics,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
September 1981,
Toxicology and applied pharmacology,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
October 2011,
Human & experimental toxicology,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
May 1985,
Canadian journal of physiology and pharmacology,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
March 1987,
Toxicology letters,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
August 2007,
Annals of the Academy of Medicine, Singapore,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
February 1986,
Toxicology and applied pharmacology,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
July 1981,
Toxicology and applied pharmacology,
G B Corcoran, and
E L Todd, and
W J Racz, and
H Hughes, and
C V Smith, and
J R Mitchell
May 1989,
The New England journal of medicine,
