Metabolism of Compound A by Renal Cysteine-S-Conjugate beta-Lyase Is Not the Mechanism of Compound A-Induced Renal Injury in the Rat
Metabolism of Compound A by Renal Cysteine-S-Conjugate beta-Lyase Is Not the Mechanism of Compound A-Induced Renal Injury in the Rat
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肾半胱氨酸-S-缀合物β-裂解酶对化合物A的代谢不是化合物A诱导大鼠肾损伤的机制
DOI：
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发表时间：
1996
影响因子：
5.7
通讯作者：
Edmond I. Eger
中科院分区：
文献类型：
--
作者：
Jackie L. Martin;M. Laster;L. Kandel;Russell L. Kerschmann;George F. Reed;Edmond I. Eger
化合物A [CF2双键C(CF3)OCH2 F]是二氧化碳吸收剂作用于七氟醚后产生的乙烯醚，可引起大鼠皮质-髓交界处坏死（外髓层外条即皮质-髓交界处损伤）。几种卤代烯烃通过将这些烯烃的谷胱甘肽偶联物转化为卤代乙酰卤化物而产生组织学上相似的皮质髓样坏死。为了验证这一机制是否解释了化合物A的肾毒性，我们阻断了导致氟硫代乙酰卤化物形成的三个代谢步骤：1)通过给予dl-丁硫氨酸-s， r -亚砜胺（BSO）来消耗谷胱甘肽；2)我们通过给予acivicin （AT-125）阻断半胱氨酸s缀合物的形成；3)通过给药氨基乙酸（AOAA）抑制肾半胱氨酸偶联β -裂解酶对肾毒性卤化物的代谢。在暴露于化合物A之前，将这些治疗单独或联合给予10或20组Wistar大鼠。我们假设阻断这些代谢步骤应减少呼吸150 ppm化合物A 3小时所产生的损伤。然而，我们发现肾脏损伤没有变化或增加，这表明该途径介导解毒而不是毒性。我们的研究结果表明，半胱氨酸- s -缀合物介导的途径不是化合物A肾毒性的机制，因此，观察到的该激活途径活性的种间差异可能与临床实践中化合物A肾毒性潜力的预测无关。（Anesth Analg 1996;82:770-4）
Compound A [CF2 double bond C(CF3)OCH2 F], a vinyl ether produced by CO2 absorbents acting on sevoflurane, can produce corticomedullary junction necrosis (injury to the outer stripe of the outer medullary layer, i.e., corticomedullary junction) in rats. Several halogenated alkenes produce a histologically similar corticomedullary necrosis by converting glutathione conjugates of these alkenes to halothionoacetyl halides. To test whether this mechanism explained the nephrotoxicity of Compound A, we blocked three metabolic steps which would lead to formation of a halothionoacetyl halide: 1) we depleted glutathione by administering dl-buthionine-S,R-sulfoximine (BSO); 2) we blocked cysteine S-conjugate formation by administering acivicin (AT-125); and 3) we inhibited subsequent metabolism by renal cysteine conjugate beta-lyase to the nephrotoxic halothionoacetyl halides by administering aminooxyacetic acid (AOAA). These treatments were given alone or in combination to separate groups of 10 or 20 Wistar rats before their exposure to Compound A. We hypothesized that blocking these metabolic steps should decrease the injury produced by breathing 150 ppm of Compound A for 3 h. However, we found either no change or an increase in renal injury, suggesting that this pathway mediates detoxification rather than toxicity. Our findings suggest that the cysteine-S-conjugate-mediated pathway is not the mechanism of Compound A nephrotoxicity and, therefore, observed interspecies differences in the activity of this activating pathway may not be relevant in the prediction of the nephrotoxic potential of Compound A in clinical practice. (Anesth Analg 1996;82:770-4)
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2-溴-2-氯-1,1-二氟乙烯的谷胱甘肽和半胱氨酸缀合物的肾毒性。
DOI：
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发表时间：
1992
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Finkelstein,MB;Baggs,RB;Anders,MW
通讯作者：
Anders,MW
吸入三氟氯乙烯和六氟丙烯对大鼠肾脏的影响。
影响因子：
3.8
作者：
Potter,CL;Gandolfi,AJ;Nagle,R;Clayton,JW
通讯作者：
Clayton,JW
影响因子：
5.9
作者：
DEKANT, W;VAMVAKAS, S
通讯作者：
VAMVAKAS, S
人肾胞质半胱氨酸缀合物 β-裂解酶活性的纯化和表征。
DOI：
--
发表时间：
1990
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Lash,LH;Nelson,RM;VanDyke,RA;Anders,MW
通讯作者：
Anders,MW
硫醇尿酸和1,4-萘醌和甲萘醌的谷胱甘肽缀合物引起的肾近端肾小管坏死的定位和程度存在差异。
影响因子：
3.8
作者：
Lau,SS;Jones,TW;Highet,RJ;Hill,BA;Monks,TJ
通讯作者：
Monks,TJ