Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol.
Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol.
复制标题
通过磺基转移酶抑制剂和普遍存在的环境污染物五氯苯酚预处理，强烈强化小鼠肝脏他莫昔芬 DNA 加合物的形成。
DOI：
10.1093/carcin/15.5.797
复制
发表时间：
1994
期刊：
影响因子：
4.7
通讯作者：
Moorthy,B
中科院分区：
文献类型：
--
作者：
Randerath,K;Bi,J;Mabon,N;Sriram,P;Moorthy,B
尽管突变试验为阴性，但临床上重要的抗雌激素药物他莫昔芬可在小鼠、大鼠和仓鼠体内诱导肝细胞DNA加合物的形成，如~(32)P-后标记所示，在大鼠体内是一种有效的肝病原。他莫昔芬的酚类和醇类代谢物已有报道。由于这些代谢物是潜在的硫酸盐协同作用的候选物质，我们检查了硫磺转移酶抑制剂五氯苯酚是否在体内调节肝脏他莫昔芬加合物的形成。雌性ICR小鼠每天口服他莫昔芬(45 mg/kg)，连续4天，有或没有ip。他莫昔芬灌胃前1h给予五氯苯酚(20 mg/kg)。在第1、2和4天，在他莫昔芬给药后5h，用改良的单磷酸版本的32P-后标记试验分析肝脏DNA Wm。在第4天，帕塔克罗酚处理导致四个他莫昔芬加合物组分的水平大幅增加(13-17倍)，而两个加合物组分似乎没有受到影响，导致总加合物形成的∼增加7倍。在第1天和第2天也观察到与五氯苯酚相关的显著增加。这种作用的机制尚未确定，但可能涉及到参与药物解毒的代谢物(S)对非亲电衍生物的硫化作用的抑制。他莫昔芬的代谢激活有两条途径，一条是敏感的，另一条是对五氯苯酚耐药的。
Although negative in assays for mutagenicity, the clinically important antiestrogen tamoxifen induces hepakic DNA adduct formation in mice, rats and hamsters, as indicated by32P-postlabeling, and is a potent hepatocardnogen in rats. Both phenolic and alcoholic metabolites of tamoxifen have been reported. As these metabolites are potential candidates for sulfate coqjugation, we examined whether the sulfe transferase inhibitor pentachlorophenol, a ubiquitous environmental contaminant, modulates hepatic tamoxifen adduct formationin vivo. Female ICR mice were given tamoxifen (45 mg/kg) daily per os for up to 4 days, with and without i.p. pretreatment with pentachloropheno1 (20 mg/kg) 1 h before dosing with tamoxifen. At days 1,2 and 4, liver DNA wm analyzed 5 h after tamoxifen administration by a modified monophosphate version of the32P-postlabeling assay. At day 4, patachrophenol pretreatment led to a large increase (13- to 17-fold) of the levels of four tamoxifen adduct fractions, while two adducts appeared unaffected, resulting in an ∼ 7-fold enhancement of overall adduct formation. Significant pentachlorophenol related increases were also observed at day 1 and day 2. The mechanism of this effect has not yet been determined, but may involve the inhibition of sulfation of a tamoxifen metabolite(s) involved in the detoxication of the drug to nonelectrophilic derivatives. It was also apparent that there are two pathways of metabolic activation of tamoxifen, one being sensitive and the other resistant to pentachlorophenol.