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首页> 外文期刊>Journal of biochemical and molecular toxicology >Metabolism of the mesoionic compound (MI-D) by mouse liver microsome, detection of its metabolite in vivo, and acute toxicity in mice.
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Metabolism of the mesoionic compound (MI-D) by mouse liver microsome, detection of its metabolite in vivo, and acute toxicity in mice.

机译：小鼠肝脏微粒体对中离子化合物（MI-D）的代谢，体内代谢物的检测以及对小鼠的急性毒性。

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摘要

The mesoionic derivative 4-phenyl-5-[4-nitrocinnamoyl]-1,3,4-thiadiazolyl-2-phenylamine chloride (MI-D) has antitumoral and anti-inflammatory effects. In this study, we present aspects of its metabolism and toxicity in mice. MI-D was metabolized in vitro by liver microsome, generating a main product with a much shorter retention time than MI-D in high-performance liquid chromatography (HPLC) analysis but with a spectrum similar to that of the original molecule. Mass spectrometry with electrospray ionization in positive mode analysis of the purified compound by HPLC indicated that the product of metabolism has four additional hydroxyl groups (m/z = 465) compared with MI-D (m/z = 401). The HPLC analyses of plasma and urine samples from mice treated with MI-D showed the presence of the metabolite product. The kinetic parameters K(m) (19.5 +/- 4.5 microM) and V(max) [1.5 +/- 0.4 units of fluorescence/(100 microg of microsomal protein/mL/s)] were estimated, confirming the metabolism of MI-D and indicating that the reaction follows Michaelis-Menten kinetics. Acute toxicity was established on the basis of an estimation of mean lethal dose (LD-50; 181.2 mg/kg) and histopathological analysis of animals that survived the LD-50 test. Abdominal adhesions, inflammatory foci, and formation of granulomas were observed. Altogether, the results contribute to the advancement of research in support of MI-D as a future chemotherapeutic drug.
机译：中离子衍生物4-苯基-5- [4-硝基肉桂酰基] -1,3,4-噻二唑基-2-苯基胺氯化物（MI-D）具有抗肿瘤和抗炎作用。在这项研究中，我们介绍了其在小鼠中的代谢和毒性方面。 MI-D在体外被肝脏微粒体代谢，生成的主要产物的保留时间比高效液相色谱（HPLC）分析中的MI-D短得多，但其光谱与原始分子的光谱相似。通过HPLC对纯化的化合物进行正模式分析的电喷雾电离质谱表明，与MI-D（m / z = 401）相比，代谢产物还具有四个附加的羟基（m / z = 465）。用MI-D处理的小鼠的血浆和尿液样品的HPLC分析表明存在代谢产物。估计动力学参数K（m）（19.5 +/- 4.5 microM）和V（max）[1.5 +/- 0.4单位荧光/（100 microg微粒体蛋白/ mL / s）]，证实MI的代谢-D，表明该反应遵循Michaelis-Menten动力学。根据对平均致死剂量（LD-50; 181.2 mg / kg）的估计以及在LD-50试验中存活的动物的组织病理学分析，确定急性毒性。观察到腹部粘连，炎性灶和肉芽肿的形成。总而言之，这些结果有助于支持MI-D作为未来化学治疗药物的研究进展。

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