Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes.
Cytotoxicity study of tacrine, structurally and pharmacologically related compounds using rat hepatocytes.
复制标题
使用大鼠肝细胞进行他克林、结构和药理学相关化合物的细胞毒性研究。
DOI：
10.3109/01480549609002197
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发表时间：
1996
影响因子：
2.6
通讯作者：
J. Theiss
中科院分区：
文献类型：
--
作者：
D. Monteith;M. Emmerling;J. Garvin;J. Theiss
他克林是第一个被批准用于治疗阿尔茨海默病的药物。大约 50% 接受他克林治疗的患者出现血清转氨酶水平升高，这是潜在肝毒性的迹象。然而，对有限数量的动物模型进行的急性和慢性研究尚未证明其肝毒性。本研究比较了他克林与结构（丙黄素和9-氨基吖啶）或药理学相似的化合物（毒扁豆碱）以及结构修饰的他克林在肝细胞培养物中的细胞毒性，以确定是否存在与毒性有关的结构活性关系。通过测定细胞外和细胞内乳酸脱氢酶的量来评估细胞毒性。在 0 至 3 mM 的测试化合物浓度范围内暴露四小时后评估细胞毒性。他克林和所有结构相关的化合物均发生浓度依赖性细胞毒性。毒扁豆碱药理相似，但结构不同，不会引起细胞毒性。细胞毒性效力似乎与乙酰胆碱酯酶抑制活性无关，而具有吖啶结构的化合物则诱导细胞毒性。因此，在该体外模型中，细胞毒性似乎与结构有关，而不是与药理作用有关。这项研究的结果表明，由于杂环结构，结构上与他克林相关的化合物具有细胞毒性。杂环化合物的芳香环的不饱和度、杂环的氨基取代、氨基的N-羟基化和环羟基化均不会显着改变细胞毒性。
Tacrine is the first drug approved for the treatment of Alzheimer's disease. Approximately 50% of patients treated with tacrine develop elevated serum aminotransferase levels, as an indication of potential hepatotoxicity. However, acute and chronic studies with a limited number of animal models have not demonstrated hepatotoxicity. The present study compared the cytotoxicity in hepatocyte cultures of tacrine with structurally (proflavine and 9-aminoacridine) or pharmacologically similar compounds (physostigmine), as well as structurally modified tacrine to determine if there was a structure activity relationship with regards to toxicity. Cytotoxicity was assessed by determination of extra- and intracellular amounts of lactate dehydrogenase. Cytotoxicity was assessed after a four-hour exposure over a test compound concentration range of 0 to 3 mM. Concentration-dependent cytotoxicity occurred with tacrine and all structurally related compounds. Physostigmine which is pharmacologically similar, but structurally different, did not induce cytotoxicity. Cytotoxic potency did not appear to be related to acetylcholinesterase inhibitory activity, while compounds with acridine structures induced cytotoxicity. Thus, in this in vitro model, cytotoxicity appears to be related to structure and not pharmacological action. Results of this study indicate that compounds structurally related to tacrine are cytotoxic because of the heterocyclic ring structure. Neither unsaturation of an aromatic ring of the heterocyclic compound, amino substitution of the heterocyclic rings, N-hydroxylation of the amino group, nor ring hydroxylation dramatically alter cytotoxicity.
使用人和大鼠肝微粒体制剂对认知激活剂他克林进行生物激活和不可逆结合。
DOI：
--
发表时间：
1993
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Woolf,TF;Pool,WF;Bjorge,SM;Chang,T;Goel,OP;Purchase2nd,CF;Schroeder,MC;Kunze,KL;Trager,WF
通讯作者：
Trager,WF
细胞色素 P-450 和含黄素的单加氧酶催化致癌物质 N-羟基-2-氨基芴的形成及其与核 DNA 的共价结合。
影响因子：
11.2
作者：
Frederick,CB;Mays,JB;Ziegler,DM;Guengerich,FP;Kadlubar,FF
通讯作者：
Kadlubar,FF