An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin.
An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin.
复制标题
苯妥英、索比尼和米安色林的微粒体代谢和细胞毒性的体外研究。
DOI：
10.1111/j.1365-2125.1988.tb05298.x
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发表时间：
1988
影响因子：
3.4
通讯作者：
BK Park
中科院分区：
文献类型：
--
作者：
RJ Riley;JL Maggs;C. Lambert;NR Kitteringham;BK Park
1.以人单核白细胞为靶细胞，研究了苯妥英钠、山梨醇和米安色林代谢产物对人和小鼠肝微粒体的细胞毒作用。台盼蓝拒染法检测细胞毒性。2.依赖NADPH的小鼠微粒体酶能将苯妥英钠和索比尼代谢成细胞毒性代谢物。环氧化物水解酶抑制剂三氯丙烷(TCPO)显著增强了这两种药物的细胞毒性。在人肝微体存在的情况下，没有观察到明显的细胞毒性。3.米安色林可被人和小鼠肝微体代谢为细胞毒素。在人肝微体存在的情况下，细胞毒性更大(13.7+/-2.2%；平均+/-S.D.4只小鼠肝微粒体的平均浓度为6.0+/-2.4%(n=4)，且不受TCPO预处理的影响。4.用放射高效液相色谱对稳定代谢产物进行定量。苯妥英钠和山梨醇在人和小鼠肝微粒体中分别被代谢为5-(对羟基苯基)-5-苯基海因(占培养放射性的0.3-0.5%)和2-羟基山梨酚(占培养放射性的0.4-2.7%)。5.米安丝氨酸在人和小鼠肝微粒体中均被代谢为8-羟基米安丝氨酸和去甲基米安丝氨酸。去甲基米安丝氨酸是与人肝微粒体孵育的主要产物(32.3+/-12%，平均值+/-S.D.)。对于四个肝脏)，而8-羟基眠丝氨酸是小鼠肝微粒体产生的主要代谢物(25.9+/-1.5%，平均值+/-S.D.，n=4)。6.通过测定与蛋白质不可逆结合的放射性标记物质的量来评估亲电代谢物的产生。只有小鼠肝微粒体能将苯妥英激活为化学反应性代谢物，而小鼠和人肝微粒体能从山梨醇和米安色林中产生反应性代谢物。7.这些研究表明，药物的细胞毒性可以通过依赖于NADPH的肝微粒体酶产生的低浓度(约微米)的代谢物来介导；然而，体外细胞毒性的证明尚未被确立为预测体内毒性的手段。
1. The cytotoxicity of metabolites generated from phenytoin, sorbinil and mianserin by human and mouse liver microsomes was assessed by co-incubation with human mononuclear leucocytes as target cells. Cytotoxicity was determined by trypan blue dye exclusion. 2. Phenytoin and sorbinil were metabolised by NADPH-dependent murine microsomal enzymes to cytotoxic metabolites. Cytotoxicity produced by both drugs was significantly enhanced by the epoxide hydrolase inhibitor trichloropropane oxide (TCPO). No significant cytotoxicity was observed in the presence of human liver microsomes. 3. Mianserin was metabolised by both human and mouse liver microsomes to a cytotoxin. Cytotoxicity was greater in the presence of human liver microsomes (13.7 +/- 2.2%; mean +/- s.d. for four livers, compared with 6.0 +/- 2.4%, mean +/- s.d., n = 4, with mouse liver microsomes), and was unaffected by pretreatment with TCPO. 4. Stable metabolites were quantified by radiometric high performance liquid chromatography. Phenytoin and sorbinil were metabolised to 5-(p-hydroxyphenyl)-5-phenyl-hydantoin (0.3-0.5% of incubated radioactivity) and 2-hydroxysorbinil (0.4-2.7% of incubated radioactivity), respectively, by both human and mouse liver microsomes. 5. Mianserin was metabolised to 8-hydroxymianserin and desmethylmianserin by both human and mouse liver microsomes. Desmethylmianserin was the major product in incubations with human liver microsomes (32.3 +/- 12%, mean +/- s.d. for four livers), whereas 8-hydroxymianserin was the predominant metabolite generated by mouse liver microsomes (25.9 +/- 1.5%, mean +/- s.d., n = 4). 6. Generation of electrophilic metabolites was assessed by determination of the amount of radiolabelled material which became irreversibly bound to protein. Only mouse liver microsomes activated phenytoin to a chemically reactive metabolite, whereas both mouse and human liver microsomes generated reactive metabolites from sorbinil and mianserin. 7. These studies show that drug cytotoxicity can be mediated by low concentrations (circa microM) of metabolites generated by NADPH-dependent hepatic microsomal enzymes; however demonstration of cytotoxicity in vitro has not been established as a means of predicting in vivo toxicity.
鼠肝胞质和微粒体环氧化物水解酶的不同底物选择性。
影响因子：
5.8
作者：
Hammock,BD;Hasagawa,LS
通讯作者：
Hasagawa,LS
苯妥英代谢成儿茶酚的 Oxygen-18 掺入研究。
DOI：
--
发表时间：
1985
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Billings,RE;Fischer,LJ
通讯作者：
Fischer,LJ