Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved.
Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved.
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[14C]他莫昔芬与肝微粒体的共价结合以及所涉及的细胞色素 P450 的形式存在物种差异。
DOI：
10.1016/0006-2952(95)98498-x
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发表时间：
1995
影响因子：
5.8
通讯作者：
L. Smith
中科院分区：
文献类型：
--
作者：
I. White;F. de Matteis;A. Gibbs;C. Lim;C. Wolf;C. Henderson;L. Smith
用人、雌性F344大鼠和DBA/2小鼠的制剂研究了依赖于NADPH的[14C]他莫昔芬与肝微粒体共价结合的物种差异。蛋白质结合已被用作代谢激活的指标和DNA结合的替代物，以确定哪些形式的细胞色素P450对遗传毒性负责。对12个人肝微粒体的9种细胞色素P450同工酶进行了鉴定和免疫定量。他莫昔芬(45μM)的结合量(25±2.5pmo1/15min/mg蛋白，均值±SE)与细胞色素P3A4和细胞色素P42B6的含量呈正相关(P<0.05)。从人乳腺肿瘤组织中也可以检测到[14C]他莫昔芬与微粒体制剂的共价结合，但结合水平比肝脏低7倍。随着底物浓度的增加，他莫昔芬与小鼠、大鼠或人肝微球制剂的共价结合增加。[14C]他莫昔芬(45μM)在大鼠体内的共价结合率是人肝微粒体制剂的3.8倍，小鼠是人肝微粒体制剂的17倍。小鼠的表观Km(9.6±1.9μM)明显低于大鼠(119±41μM)。用苯巴比妥或地塞米松处理雌性大鼠，与对照组相比，[14C]他莫昔芬结合量增加了4-5倍，这与CYP2B1和CYP3A1参与代谢激活是一致的。如果相同的反应性代谢物参与蛋白质和DNA的结合，目前还不能区分。与大鼠相比，小鼠肝微粒体激活他莫昔芬的更大潜力并不反映体内服用他莫昔芬后出现的DNA损伤或肝癌致癌性。结论：三苯氧胺体外与蛋白质的共价结合与该化合物的致癌潜能无直接关系。然而，在所调查的三个物种中，结果表明，无论是在动力学参数还是代谢产物的模式方面，大鼠都是比小鼠更好的人肝微粒体激活他莫昔芬的模型。
Species differences in the NADPH-dependent covalent binding of [14C]tamoxifen to liver microsomes have been studied using preparations from humans, female F344 rats and DBA/2 mice. Protein binding has been used as an index of metabolic activation and as a surrogate for DNA binding in order to establish which forms of cytochrome P450 are responsible for genotoxicity. A panel of 12 human liver microsomes has been characterized and immunoquantified for nine cytochrome P450 isoenzymes. Binding of tamoxifen (45 μM) (25 ± 2.5 pmol/15 min/mg protein, mean ± SE) correlated (P < 0.05) with CYP3A4 and CYP2B6 content. Covalent binding of [14C]tamoxifen to microsomal preparations from human breast tumour tissue could also be detected but at levels 7-fold lower than in liver. The covalent binding of tamoxifen to mice, rat or human liver microsomal preparations increased with increasing substrate concentration. Covalent binding of [14C]tamoxifen (45 μM) in rats was 3.8-fold and mice 17-fold higher than in human liver microsomal preparations. In mice, the apparent Km(9.6 ± 1.9 μM) was very much lower than for rats (119 ± 41 μM). Pretreatment of female rats with phenobarbitone or dexamethasone resulted in a 4- to 5-fold increase in [14C]tamoxifen binding, relative to controls, consistent with the involvement of CYP2B1 and CYP3A1 in the metabolic activation. It cannot be distinguished at present if the same reactive metabolites are involved in protein and DNA binding. The greater potential of mouse liver microsomes to activate tamoxifen, relative to rats, does not reflect DNA damage or hepatocarcinogenicity seen following dosing with tamoxifen in vivo. It is concluded that covalent binding of tamoxifen to protein in vitro cannot be directly related to the carcinogenic potential of this compound. However, in the three species investigated, results suggest that the rat is a better model than the mouse for human liver microsomal activation of tamoxifen both with respect to kinetic parameters and the pattern of metabolic products.
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抗乳腺癌抗雌激素剂他莫昔芬的代谢。
DOI：
--
发表时间：
1993
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Mani,C;Hodgson,E;Kupfer,D
通讯作者：
Kupfer,D
他莫昔芬与大鼠和人肝微粒体激活系统形成 DNA 加合物。
影响因子：
4.7
作者：
Pathak,DN;Bodell,WJ
通讯作者：
Bodell,WJ
抗乳腺癌抗雌激素剂他莫昔芬的代谢。
DOI：
--
发表时间：
1993
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Mani,C;Gelboin,HV;Park,SS;Pearce,R;Parkinson,A;Kupfer,D
通讯作者：
Kupfer,D
他莫昔芬在啮齿动物中诱导共价 DNA 加合物。
影响因子：
11.2
作者：
Han,XL;Liehr,JG
通讯作者：
Liehr,JG
细胞色素 P-450 介导的激活以及抗雌激素他莫昔芬与大鼠和人肝脏中蛋白质的不可逆结合：含黄素单加氧酶可能参与他莫昔芬的激活。
影响因子：
11.2
作者：
Mani,C;Kupfer,D
通讯作者：
Kupfer,D