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首页> 外文OA文献 >Metabolism of ciamexon by human liver microsomes: an investigation into the formation of stable, chemically reactive and cytotoxic metabolites.
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Metabolism of ciamexon by human liver microsomes: an investigation into the formation of stable, chemically reactive and cytotoxic metabolites.

机译：人肝微粒体对ciamexon的代谢：对稳定，化学反应性和细胞毒性代谢物形成的研究。

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1. The in vitro generation of stable, protein-reactive and cytotoxic metabolites from ciamexon by human liver microsomes has been assessed. Stable metabolites were characterized by h.p.l.c./mass spectrometry, protein reactive metabolites by radiometric analysis and cytotoxic metabolites by assessment of cell viability after exposure to metabolites formed in situ. 2. Human livers were obtained from renal transplant donors. All 16 livers investigated metabolized ciamexon in a NADPH-dependent reaction, the major metabolite being the 6-hydroxy-methyl derivative. The hydroxylase activity of the livers varied from 34-577 pmol mg-1 min-1, with a mean activity of 306 +/- 156 pmol mg-1 min-1. The further oxidation product, 6-carboxy ciamexon, was also detected in some incubations. A third, unidentified, polar metabolite was present in all incubations (3.34-11.11% of incubated radioactivity). 3. Only very low levels (less than 1%) of radioactivity became irreversibly bound to microsomal protein, which suggests that ciamexon undergoes little or no oxidative bioactivation in vitro. 4. Human liver microsomes did not metabolize ciamexon to a cytotoxic species, whereas microsomes prepared from mouse livers did generate a cytotoxic species. The degree of toxicity was enhanced if animals were pre-treated with either phenobarbitone or beta-naphthoflavone.
机译：1.已评估了人肝微粒体从cimexon体外生成稳定的，蛋白反应性和细胞毒性代谢产物的能力。稳定的代谢物通过h.p.l.c./质谱法进行表征，蛋白质活性代谢物通过放射分析进行分析，细胞毒性代谢物通过暴露于原位形成的代谢产物后评估细胞生存力来表征。 2.人肝是从肾移植供体中获得的。所有16个肝脏均在NADPH依赖性反应中研究了代谢的cimexon，主要代谢物是6-羟基-甲基衍生物。肝脏的羟化酶活性为34-577 pmol mg-1 min-1，平均活性为306 +/- 156 pmol mg-1 min-1。在某些孵化中还检测到了进一步的氧化产物6-羧基ciamexon。在所有培养中均存在第三种不确定的极性代谢产物（占所培养放射性的3.34-11.11％）。 3.只有极低水平（小于1％）的放射性不可逆地结合到微粒体蛋白上，这表明ciamexon在体外几乎没有或根本没有氧化生物激活。 4.人肝微粒体不会将ciamexon代谢为细胞毒性物质，而由小鼠肝脏制备的微粒体确实会产生细胞毒性物质。如果用苯巴比妥或β-萘黄酮对动物进行预处理，则毒性程度会提高。

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    Tingle, M D; Park, B K;

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  • 年度 1990
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