Stern Stephan T, Bruno Mary K, Horton Robert A, Hill Dennis W, Roberts Jeanette C, Cohen Steven D
Toxicology Program, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06268, USA.
Toxicol Appl Pharmacol. 2005 Jan 15;202(2):160-71. doi: 10.1016/j.taap.2004.06.029.
Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Our recent investigations have focused on the possible involvement of glutathione-derived APAP metabolites in APAP nephrotoxicity and have demonstrated that administration of acetaminophen-cysteine (APAP-CYS) potentiated APAP-induced renal injury with no effects on APAP-induced liver injury. Additionally, APAP-CYS treatment alone resulted in a dose-responsive renal GSH depletion. This APAP-CYS-induced renal GSH depletion could interfere with intrarenal detoxification of APAP or its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) and may be the mechanism responsible for the potentiation of APAP nephrotoxicity. Renal-specific GSH depletion has been demonstrated in mice and rats following administration of amino acid gamma-glutamyl acceptor substrates for gamma-glutamyl transpeptidase (gamma-GT). The present study sought to determine if APAP-CYS-induced renal glutathione depletion is the result of disruption of the gamma-glutamyl cycle through interaction with gamma-GT. The results confirmed that APAP-CYS-induced renal GSH depletion was antagonized by the gamma-glutamyl transpeptidase (gamma-GT) inhibitor acivicin. In vitro analysis demonstrated that APAP-CYS is a gamma-glutamyl acceptor for both murine and bovine renal gamma-GT. Analysis of urine from mice pretreated with acivicin and then treated with APAP, APAP-CYS, or acetaminophen-glutathione identified a gamma-glutamyl-cysteinyl-acetaminophen metabolite. These findings are consistent with the hypothesis that APAP-CYS contributes to APAP nephrotoxicity by depletion of renal GSH stores through interaction with the gamma-glutamyl cycle.
对乙酰氨基酚（APAP）的肾毒性在人类和实验动物中均有观察到。我们最近的研究聚焦于谷胱甘肽衍生的APAP代谢产物在APAP肾毒性中可能的作用，并已证明给予对乙酰氨基酚 - 半胱氨酸（APAP - CYS）会增强APAP诱导的肾损伤，而对APAP诱导的肝损伤无影响。此外，单独给予APAP - CYS治疗会导致剂量依赖性的肾谷胱甘肽（GSH）耗竭。这种APAP - CYS诱导的肾GSH耗竭可能会干扰APAP或其有毒代谢产物N - 乙酰 - 对苯醌亚胺（NAPQI）的肾内解毒作用，并且可能是APAP肾毒性增强的机制。在给予γ - 谷氨酰转肽酶（γ - GT）的氨基酸γ - 谷氨酰受体底物后，已在小鼠和大鼠中证明了肾特异性GSH耗竭。本研究旨在确定APAP - CYS诱导的肾谷胱甘肽耗竭是否是通过与γ - GT相互作用破坏γ - 谷氨酰循环的结果。结果证实，γ - 谷氨酰转肽酶（γ - GT）抑制剂阿西维辛可拮抗APAP - CYS诱导的肾GSH耗竭。体外分析表明，APAP - CYS是小鼠和牛肾γ - GT的γ - 谷氨酰受体。对先用阿西维辛预处理然后用APAP、APAP - CYS或对乙酰氨基酚 - 谷胱甘肽处理的小鼠尿液分析，鉴定出一种γ - 谷氨酰 - 半胱氨酰 - 对乙酰氨基酚代谢产物。这些发现与以下假设一致，即APAP - CYS通过与γ - 谷氨酰循环相互作用消耗肾GSH储备，从而导致APAP肾毒性。
