Evidence against deacetylation and for cytochrome P450-mediated activation in acetaminophen-induced nephrotoxicity in the CD-1 mouse.
Evidence against deacetylation and for cytochrome P450-mediated activation in acetaminophen-induced nephrotoxicity in the CD-1 mouse.
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CD-1 小鼠中对乙酰氨基酚诱导的肾毒性中反对脱乙酰化和细胞色素 P450 介导的激活的证据。
DOI：
10.1016/0041-008x(91)90325-9
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发表时间：
1991
影响因子：
3.8
通讯作者：
Cohen,SD
中科院分区：
文献类型：
--
作者：
EmeighHart,SG;Beierschmitt,WP;Bartolone,JB;Wyand,DS;Khairallah,EA;Cohen,SD
对乙酰氨基酚（APAP）给药（600 mg/kg，po）导致禁食18小时的3月龄雄性CD-1小鼠近端肾小管坏死。本研究旨在确定APAP脱乙酰化为对氨基苯酚（PAP）是否是小鼠肾毒性的先决条件，正如Fischer大鼠一样。给药后12小时，APAP或PAP给药导致小鼠血浆尿素氮显著升高，近端肾小管明显坏死。羧酸酯酶抑制剂磷酸二（对硝基苯基）酯或磷酸三邻甲苯酯对APAP去乙酰化的抑制并没有改变APAP的肝毒性或肾毒性。相比之下，用MFO抑制剂胡椒基丁醚预处理可降低APAP的肾毒性，但不能降低PAP的肾毒性。APAP处理的小鼠肾脏的免疫化学分析表明共价结合的APAP，但没有结合后，小鼠用肾毒性剂量的PAP处理。由于所用抗体的特征在于主要针对结合的APAP代谢物的N-乙酰基部分，并且由于其不与给予肾毒性剂量PAP的小鼠的肾蛋白反应，因此APAP脱乙酰化不可能先于结合或结合的PAP发生乙酰化。总之，这些结果表明，在CD-1小鼠中，APAP诱导的肾毒性与先前描述的Fischer大鼠不同，可能涉及细胞色素P450依赖性激活和随后的代谢物共价结合，而无需预先脱乙酰化。
Acetaminophen (APAP) administration (600 mg/kg, po) results in proximal tubular necrosis in 18-hr fasted, 3-month-old male CD-1 mice. This study was undertaken to determine if deacetylation of APAP to p-aminophenol (PAP) is a prerequisite to nephrotoxicity in the mouse, as it is in the Fischer rat. Administration of either APAP or PAP to mice resulted in significant elevations of plasma urea nitrogen and marked proximal tubular necrosis at 12 hr after dosing. Prior inhibition of APAP deacetylation by the carboxylesterase inhibitors bis(p-nitrophenyl) phosphate or tri-o-tolyl-phosphate did not alter APAP hepatotoxicity or nephrotoxicity. By contrast, pretreatment with the MFO inhibitor piperonyl butoxide decreased APAP nephrotoxicity but not that of PAP. Immunochemical analysis of kidneys from APAP-treated mice demonstrated covalently bound APAP but no binding was detected after mice were treated with a nephrotoxic dose of PAP. Since the antibody used has been characterized as being directed primarily against the N-acetyl moiety of bound APAP metabolite and since it did not react with kidney proteins of mice given a nephrotoxic dose of PAP, it is unlikely that APAP deacetylation preceded binding or that acetylation of bound PAP occurred. Taken together, these findings indicate that in the CD-1 mouse, APAP-induced nephrotoxicity differs from that previously described for the Fischer rat and likely involves cytochrome P450-dependent activation and subsequent covalent binding of a metabolite without prior deacetylation.
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对乙酰氨基酚代谢物与肾蛋白的共价结合和肾谷胱甘肽的消耗。
影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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