Reicks M, Calvert R J, Hathcock J N
Division of Nutrition, Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204.
Drug Nutr Interact. 1988;5(4):351-63.
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.
给成年瑞士韦伯斯特小鼠喂食对乙酰氨基酚（ACAP）4周，以研究长期摄入ACAP对肝脏中还原型谷胱甘肽（GSH）浓度的影响。在第一个实验中，将雄性和雌性小鼠配对喂食含ACAP的饲料，其含量按干重计分别为日粮的0.0（对照）、0.3、0.6和1.0%，日粮中总硫氨基酸含量为日粮的0.5%。肝脏GSH被消耗，随着ACAP剂量增加，以尿中ACAP-GSH衍生共轭物形式排泄的剂量百分比呈剂量依赖性增加。给予1.0%ACAP的组中，血清谷丙转氨酶活性、相对肝脏重量和肝脏微粒体蛋白含量增加，但微粒体苯胺羟化作用降低。在第二个实验中，给成年雄性小鼠随意喂食含0.0或0.6%ACAP的饲料，总L-蛋氨酸含量分别为0.25、0.5（需要量水平）或1.0%。除接受1.0%蛋氨酸的组外，所有组在开始ACAP处理1周后肝脏GSH均显著消耗。这种降低在整个4周处理期持续存在。4周后，由于ACAP摄入和蛋氨酸缺乏，肝脏半胱氨酸也减少，而血清无机硫酸盐浓度未改变。日粮中1.0%的蛋氨酸也可防止肝脏半胱氨酸水平降低。GSH的剂量依赖性消耗、ACAP-GSH衍生共轭物排泄增加的趋势以及通过提供超过需要量的日粮蛋氨酸来防止GSH消耗表明，长期摄入ACAP可能会增加对含硫氨基酸的需求，并限制蛋氨酸和半胱氨酸用于蛋白质合成、甲基化反应和药物解毒的可用性。
