关于L(αS,5S)-α-氨基-3-氯-4,5-二氢-5-异恶唑乙酸（AT-125）对费希尔344大鼠4-氨基苯酚诱导的肾毒性影响的研究。

Studies on the effects of L(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) on 4-aminophenol-induced nephrotoxicity in the Fischer 344 rat.

作者信息

Anthony M L, Beddell C R, Lindon J C, Nicholson J K

机构信息

Department of Chemistry, Birkbeck College, University of London, UK.

出版信息

Arch Toxicol. 1993;67(10):696-705. doi: 10.1007/BF01973694.

DOI:10.1007/BF01973694

PMID:7907856

Abstract

4-Aminophenol (para-aminophenol; PAP) causes selective necrosis to the S3 segment of the proximal tubule in experimental animals. The mechanism of PAP nephrotoxicity has not been fully elucidated, although it has been suggested to involve glutathione (GSH)-dependent S-conjugation followed by processing by the enzyme gamma-glutamyl transpeptidase (gamma GT) to the corresponding cysteine S-conjugate. This proposed toxicity mechanism was probed further by administering L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), a potent gamma GT inhibitor, to Fischer 344 (F344) rats before treatment with PAP (100 mg/kg). AT-125 pretreatment did not appear to protect against PAP-induced nephrotoxicity as assessed by renal histopathology, clinical chemistry and proton nuclear magnetic resonance (1H NMR) spectroscopy of urine. These data suggest that renal gamma GT activity is not a prerequisite for PAP nephrotoxicity and that the generation of a cysteine S-conjugate is not a unique requirement for the induction of PAP nephrotoxicity.

摘要

4-氨基苯酚（对氨基苯酚；PAP）在实验动物中会导致近端肾小管S3段发生选择性坏死。尽管有人提出PAP肾毒性的机制涉及谷胱甘肽（GSH）依赖性S-结合，随后由γ-谷氨酰转肽酶（γGT）将其加工成相应的半胱氨酸S-结合物，但PAP肾毒性的机制尚未完全阐明。通过在给予PAP（100 mg/kg）之前向Fischer 344（F344）大鼠施用L-（αS，5S）-α-氨基-3-氯-4,5-二氢-5-异恶唑乙酸（AT-125）（一种有效的γGT抑制剂），对这一提出的毒性机制进行了进一步探究。通过肾脏组织病理学、临床化学以及尿液的质子核磁共振（1H NMR）光谱评估，AT-125预处理似乎并未预防PAP诱导的肾毒性。这些数据表明，肾脏γGT活性不是PAP肾毒性的先决条件，并且半胱氨酸S-结合物的生成不是诱导PAP肾毒性的唯一必要条件。