DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems.
DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems.
复制标题
他莫昔芬与大鼠和人肝微粒体激活系统形成 DNA 加合物。
DOI：
10.1093/carcin/15.3.529
复制
发表时间：
1994
期刊：
影响因子：
4.7
通讯作者：
Bodell,WJ
中科院分区：
文献类型：
--
作者：
Pathak,DN;Bodell,WJ
使用大鼠和人肝脏微粒体制剂，我们研究了抗雌激素化合物他莫昔芬（TMX）形成DNA加合物的活化。用苯巴比妥对大鼠进行预处理可增加TMX微粒体活化3- 6倍的DNA加合物形成，这取决于所用的辅因子。当还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）在人和大鼠微粒体活化系统中用作辅因子时，DNA加合物的相对水平分别为2.9和5.2 × 10− 8，23 P后标记检测到1-3个TMX-DNA加合物; DNA加合物1在两种微粒体系统中相同。当使用氢过氧化枯烯（CuOOH）作为辅因子时，TMX的活化在大鼠和人肝微粒体中产生了四种主要的DNA加合物和几种次要的DNA加合物;相对加合物水平分别为11.1和23.1 × 10 − 8。TMX-DNA加合物1、4、5和6在人和大鼠微粒体系统中相似，CuOOH为辅因子。与NADPH作为辅因子形成的TMX-DNA加合物明显不同于与CuOOH作为辅因子形成的TMX-DNA加合物，这意味着导致单个DNA加合物的代谢物不同。在活化体系中加入P450抑制剂正辛胺或α-萘异硫氰酸酯可使加合物的形成减少70- 93%。我们提出，TMX-DNA加合物形成的NADPH作为辅因子的结果从P450作为一个单加氧酶，而与CuOOH作为辅因子的结果从P450作为一个过氧化物酶。我们的研究结果表明，可能需要进一步的研究，以确定TMX治疗的妇女化疗以外的目的的安全性。
Using microsomal preparations from rat and human liver, we investigated the activation of the anti-estrogen compound tamoxifen (TMX) to form DNA adducts. Pretreatment of rats with phenobarbital increased DNA adduct formation by microsomal activation of TMX 3- to 6-fold, depending on the cofactors used. When reduced nicotinamide-adenine dinucleotide phosphate (NADPH) was used as a cofactor in human and rat microsomal activation systems, the relative DNA adduct levels were 2.9 and 5.2 × 10−8respectively and 1-3 TMX-DNA adducts were detected by23P-postlabeling; DNA adduct 1 was the same in both microsomal systems. When cumene hydroperoxide (CuOOH) was used as a cofactor, activation of TMX produced four major DNA adducts and several minor DNA adducts in both rat and human liver microsomes; the relative adduct levels were 11.1 and 23.1 ×lO−8respectively. TMX-DNA adducts 1, 4, 5 and 6 were similar in both human and rat microsomal systems with CuOOH as the cofactor. The TMX-DNA adducts formed with NADPH as the cofactor were clearly different from those formed with CuOOH as the cofactor, which implies that the metabolites leading to the individual DNA adducts were different. Addition of a P450 inhibitor, eithern-octylamine or α-napthylisothiocyanate, to the activation system reduced adduct formation by 70–93%. We propose that the TMX-DNA adducts formed with NADPH as the cofactor result from P450 acting as a mono-oxygenase, whereas the adducts formed with CuOOH as the cofactor result from P450 acting as a peroxidase. Our findings suggest that further studies may be required to establish the safety of TMX treatment of women for purposes other than chemotherapy.