Effects of prolonged acetaminophen ingestion and dietary methionine on mouse liver glutathione.
Acetaminophen (ACAP) was fed to adult Swiss-Webster mice for 4 weeks to examine the effect of prolonged ACAP ingestion on hepatic reduced glutathione (GSH) concentrations. In the first experiment, male and female mice were pair-fed diets containing ACAP at levels of 0.0 (control), 0.3, 0.6, and 1.0% of diet on a dry weight basis with the total sulfur-amino acids provided at 0.5% of the diet. Hepatic GSH was depleted, and the percentage of dose excreted as the urinary ACAP-GSH-derived conjugate increased in a dose-dependent manner with increasing ACAP. Serum glutamic-pyruvic transaminase activity, relative liver weight, and hepatic microsomal protein content increased in the group given 1.0% ACAP, but microsomal aniline hydroxylation decreased. In the second experiment, adult male mice were fed ad libitum diets containing 0.0 or 0.6% ACAP with total L-methionine provided at 0.25, 0.5 (requirement level), or 1.0%. Hepatic GSH was markedly depleted 1 week after initiation of ACAP treatment in all groups except those receiving 1.0% methionine. This reduction persisted throughout the 4-week treatment period. After 4 weeks, liver cysteine was also reduced as a result of ACAP ingestion and methionine deficiency, whereas serum inorganic sulfate concentration was not changed. Reduction in hepatic cysteine levels was also prevented by 1.0% dietary methionine. The dose-dependent depletion of GSH, the trend toward an increase in ACAP-GSH-derived conjugate excretion, and the prevention of GSH depletion by providing dietary methionine in excess of requirement indicate that prolonged ingestion of ACAP may increase the requirement for sulfur-containing amino acids and limit the availability of methionine and cysteine for protein synthesis, methylation reactions, and drug detoxification.
Reicks
M
M
Division of Nutrition, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204.
Calvert
R J
RJ
Hathcock
J N
JN
D000082:Acetaminophen / Q000008:administration & dosage / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004032:Diet; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology
D000082:Acetaminophen; D008715:Methionine; D000815:Aniline Hydroxylase; D000410:Alanine Transaminase; D005978:Glutathione; D003545:Cysteine