Formation and disposition of nitrosochloramphenicol in rat liver.
Formation and disposition of nitrosochloramphenicol in rat liver.
复制标题
亚硝基氯霉素在大鼠肝脏中的形成和分布。
DOI：
10.1016/0006-2952(85)90242-4
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发表时间：
1985
影响因子：
5.8
通讯作者：
H. Kampffmeyer
中科院分区：
文献类型：
--
作者：
M. Ascherl;P. Eyer;H. Kampffmeyer
有人认为，在氯霉素诱导的再生障碍性贫血亚硝基氯霉素可能涉及作为一个有毒的中间体。我们发现，氨基氯霉素，据报道，由氯霉素形成的肠道细菌，是N-氧化的未处理大鼠的肝微粒体的表观Km = 0.4 mM和Vmax = 0.28 nmole/min/mg蛋白。这些值与苯胺N-氧化报道的那些密切一致。然而，还原反应以明显更高的速率消除N-氧化产物。根据无血红蛋白单次肝脏灌注实验判断，N-羟基氯霉素的还原速率快于300 nmole/min/g肝脏湿重，亚硝基氯霉素的消除速率快于1.5 μmole/min/g肝脏。至少两种NADPH和两种NADH依赖性胞质酶负责亚硝基氯霉素的还原。通过停流分析确定这些酶的动力学参数揭示了酶的贡献，其中之一是醇脱氢酶，米氏常数在微摩尔范围内。尽管这种高还原能力，约10%的亚硝基氯霉素与GSH反应，形成谷胱甘肽亚磺酰胺氯霉素和GSSG从肝脏释放到胆汁和静脉流出物。在高亚硝基氯霉素负荷下，这些反应导致肝脏谷胱甘肽耗竭，引起膜损伤，并损害胆汁生成。在低亚硝基氯霉素负荷下，即低于0.5 μmole/min/g，没有相关的亚硝基氯霉素通过肝脏。这些数据以及先前报告的亚硝基氯霉素在人体血液中的反应表明，亚硝基氯霉素如果在肠或肝脏中形成，则不太可能转移到关键靶点。
It has been suggested that in the chloramphenicol-induced aplastic anemia nitrosochloramphenicol may be involved as a toxic intermediate. We found that aminochloramphenicol, which reportedly is formed from chloramphenicol by intestinal bacteria, is N-oxygenated by liver microsomes of untreated rats with apparentKm= 0.4 mM andVmax= 0.28 nmole/min/mg protein. These values are in close agreement with those reported for aniline N-oxygenation. Reductive reactions, however, eliminate the N-oxygenation products at markedly higher rates. As judged from hemoglobin-free singlepass liver perfusion experiments, N-hydroxy-chloramphenicol is reduced at rates faster than 300 nmole/min/g liver wet, and nitrosochloramphenicol is eliminated at rates faster than 1.5 μmole/min/g liver. At least two NADPH- and two NADH-dependent cytosolic enzymes are responsible for nitrosochloramphenicol reduction. Determination of the kinetic parameters of these enzymes by stop-flow analysis revealed the contribution of enzymes, one of it being alcohol dehydrogenase, with Michaelis constants in the micromolar range. Despite this high reducing capacity, about 10% of nitrosochloramphenicol reacted with GSH under formation of glutathionesulfinamidochloramphenicol and GSSG released from the liver into bile and venous effluent. At high nitrosochloramphenicol load these reactions led to glutathione depletion of the liver, caused membrane damage, and impaired bile production. At low nitrosochloramphenicol load, i.e. below 0.5 μmole/min/g, no relevant nitrosochloramphenicol passed the liver. These data together with the previously reported reactions of nitrosochloramphenicol within human blood suggest that nitrosochloramphenicol, if formed at all in the intestine or liver, is rather unlikely to be transferred to the critical target.
亚硝基氯霉素抑制线粒体中的质子易位。
影响因子：
5.8
作者：
Abou-Khalil,S;Abou-Khalil,WH;Yunis,AA
通讯作者：
Yunis,AA
氯霉素介导的 DNA 损伤及其在氯霉素对 DNA 合成的抑制作用中的可能作用。
DOI：
--
发表时间：
1983
期刊：
The Journal of laboratory and clinical medicine
影响因子：
--
作者：
Murray,TR;Downey,KM;Yunis,AA
通讯作者：
Yunis,AA
大鼠肝微粒体制剂酶促还原氯霉素和亚硝基氯霉素。
影响因子：
3.1
作者：
Lim,LO;Yunis,AA
通讯作者：
Yunis,AA