Lauterburg B H, Mitchell J R
J Hepatol. 1987 Apr;4(2):206-11. doi: 10.1016/s0168-8278(87)80081-8.
In spite of the importance of glutathione (GSH) in the detoxification of toxic metabolites of drugs, virtually nothing is known about the regulation of hepatic GSH homeostasis in man. In order to estimate the turnover of hepatic GSH and to assess the effect of different doses of acetaminophen (paracetamol) on the synthesis of GSH in man, [3H]cystine and varying doses of acetaminophen were administered to healthy volunteers, and the time course of the specific activity of the cysteine moiety of N-acetylcysteinyl-acetaminophen excreted in urine was followed. The fractional rate of turnover of the tracer in N-acetylcysteinyl-acetaminophen increased significantly from 0.031 +/- 0.007 h-1 after doses of acetaminophen ranging from 50 to 300 mg to 0.045 +/- 0.011 and 0.121 +/- 0.027 h-1 following 600 and 1200 mg of acetaminophen, respectively. The data indicate that therapeutic doses of acetaminophen markedly stimulate the rate of turnover of the pool of cysteine available for the synthesis of GSH, most likely due to an increased rate of synthesis of GSH which is required to detoxify the toxic metabolite of acetaminophen. Patients who are not able to respond to a similar demand on their stores of GSH by increasing the synthesis of GSH may be at higher risk of developing hepatic injury from drugs that require GSH for their detoxification.
尽管谷胱甘肽（GSH）在药物毒性代谢产物的解毒过程中具有重要作用，但对于人体肝脏中GSH稳态的调节却几乎一无所知。为了评估肝脏GSH的周转率，并评估不同剂量对乙酰氨基酚（扑热息痛）对人体GSH合成的影响，向健康志愿者施用了[3H]胱氨酸和不同剂量的对乙酰氨基酚，并跟踪了尿中排泄的N - 乙酰半胱氨酰 - 对乙酰氨基酚中半胱氨酸部分的比活性随时间的变化过程。在对乙酰氨基酚剂量为50至300毫克时，N - 乙酰半胱氨酰 - 对乙酰氨基酚中示踪剂的周转率分数从0.031±0.007 h-1显著增加到分别服用600毫克和1200毫克对乙酰氨基酚后的0.045±0.011 h-1和0.121±0.027 h-1。数据表明，治疗剂量的对乙酰氨基酚显著刺激了可用于合成GSH的半胱氨酸池的周转率，这很可能是由于为了对乙酰氨基酚的毒性代谢产物进行解毒而需要增加GSH的合成速率。那些无法通过增加GSH的合成来应对其GSH储备的类似需求的患者，可能因需要GSH进行解毒的药物而面临更高的肝损伤风险。
