Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.
Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity II. Possible involvement of the gamma-glutamyl cycle.
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对乙酰氨基酚-半胱氨酸对对乙酰氨基酚肾毒性的影响 II。
DOI：
10.1016/j.taap.2004.06.029
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发表时间：
2005
影响因子：
3.8
通讯作者：
Cohen,StevenD
中科院分区：
文献类型：
--
作者：
Stern,StephanT;Bruno,MaryK;Horton,RobertA;Hill,DennisW;Roberts,JeanetteC;Cohen,StevenD
对乙酰氨基酚（APAP）肾毒性已在人类和研究动物中观察到。我们最近的研究集中在谷胱甘肽衍生的APAP代谢产物在APAP肾毒性的可能参与，并已证明，对乙酰氨基酚-半胱氨酸（APAP-CYS）的管理增强APAP诱导的肾损伤，对APAP诱导的肝损伤没有影响。此外，单独APAP-CYS治疗导致剂量反应性肾GSH耗竭。这种APAP-CYS诱导的肾脏GSH耗竭可干扰APAP或其毒性代谢产物N-乙酰基-对苯醌亚胺（NAPQI）的肾内解毒，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实了肾特异性GSH耗竭。本研究旨在确定APAP-CYS诱导的肾脏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acivicin可拮抗APAP-CYS诱导的肾脏GSH耗竭。体外分析表明，APAP-CYS是鼠和牛肾γ-GT的γ-谷氨酰受体。对用阿西维星预处理然后用APAP、APAP-CYS或对乙酰氨基酚-谷胱甘肽处理的小鼠的尿液进行分析，鉴定出γ-谷氨酰-半胱氨酰-对乙酰氨基酚代谢物。这些发现与以下假设一致：APAP-CYS通过与γ-谷氨酰循环相互作用消耗肾脏GSH储存而导致APAP肾毒性。
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 γ-glutamyl acceptor substrates for γ-glutamyl transpeptidase (γ-GT). The present study sought to determine if APAP-CYS-induced renal glutathione depletion is the result of disruption of the γ-glutamyl cycle through interaction with γ-GT. The results confirmed that APAP-CYS-induced renal GSH depletion was antagonized by the γ-glutamyl transpeptidase (γ-GT) inhibitor acivicin. In vitro analysis demonstrated that APAP-CYS is a γ-glutamyl acceptor for both murine and bovine renal γ-GT. Analysis of urine from mice pretreated with acivicin and then treated with APAP, APAP-CYS, or acetaminophen-glutathione identified a γ-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 γ-glutamyl cycle.
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影响因子：
3.8
作者：
A. Standeven;K. Wetterhahn
通讯作者：
A. Standeven;K. Wetterhahn
非再循环大鼠肝脏灌注中半胱氨酰白三烯的代谢。
DOI：
10.1111/j.1432-1033.1989.tb14701.x
发表时间：
1989
期刊：
European journal of biochemistry
影响因子：
--
作者：
M. Wettstein;Wolfgang Gerok;D. Häussinger
通讯作者：
D. Häussinger
γ-谷氨酰氨基酸抑制γ-谷氨酰转肽酶并诱导谷胱甘肽尿。
DOI：
10.1073/pnas.83.14.5029
发表时间：
1986
影响因子：
11.1
作者：
M. Anderson;A. Meister
通讯作者：
A. Meister
DOI：
10.1016/0006-291x(80)90557-4
发表时间：
1980-01-01
影响因子：
3.1
作者：
REED, DJ;ELLIS, WW;MECK, RA
通讯作者：
MECK, RA
对乙酰氨基酚对 CD-1 小鼠的肾毒性。
DOI：
10.1006/taap.1996.0020
发表时间：
1996
期刊：
Toxicology and applied pharmacology.
影响因子：
--
作者：
EmeighHart,SG;Wyand,DS;Khairallah,EA;Cohen,SD
通讯作者：
Cohen,SD