Metabolism and DNA binding of benzo(a)pyrene in vivo in the rat.
Metabolism and DNA binding of benzo(a)pyrene in vivo in the rat.
复制标题
大鼠体内苯并(a)芘的代谢和 DNA 结合。
作者：
M. Boroujerdi;H. Kung;A. Wilson;M. Anderson
本文研究了苯并（a）芘（BP）在雄性SD大鼠体内的代谢和DNA结合。BP以1.0和10.0 µmol/kg的剂量水平静脉给药。从[ 3 H] BP处理大鼠的DNA样品进行酶消化脱氧核糖核苷和高压液相色谱分析。在肺中观察到几种色谱上不同的核苷结合加合物，而在肝脏中仅观察到一种加合物。肺中形成的主要加合物与肝中形成的加合物在色谱上相同，分别占肺和肝中总DNA结合的42%和7%。主要加合物（II）似乎是由BP酚类的进一步代谢产生的。在大鼠肝脏中未检测到BP双羟环氧加合物，在大鼠肺中仅观察到相对少量的BP双羟环氧加合物，占总DNA结合的1.4%。在大鼠肺中缺乏大量BP二醇-三氧化二烯加合物的形成与BP在大鼠中明显缺乏肺肿瘤诱导一致。两个剂量水平下的BP-DNA加合物特征相似。在体内观察到的BP-DNA加合物的配置文件和配置文件在各种体外模型系统之间的比较。在BP静脉给药后，从胆汁插管动物中采集胆汁样本。当BP剂量为1.0 µmol/kg时，68%的剂量在6小时内排泄到胆汁中，其中34%和9%分别为葡糖苷酸和硫酸盐结合物。其余胆汁代谢物可能为谷胱甘肽结合物。在胆汁中检测到酚类、二醇类、醌类和未表征的极性更强的代谢产物（前9、10）的葡糖苷酸和硫酸盐结合物。苯并（a）芘-3，6-二酮（剂量的6.5%）和前9、10、9%剂量是主要的葡糖苷酸代谢产物。前9、10代谢物可能是通过单加氧酶再循环的多羟基化BP衍生物。加合物II可能是由DNA与前9，10代谢物形成过程中产生的活性中间体相互作用形成的。
Abstract The in vivo metabolism and DNA binding of benzo( a )pyrene (BP) was examined in male Sprague-Dawley rat. BP was administered i.v. at dose levels of 1.0 and 10.0 µmol/kg. DNA samples from [ 3 H]BP-treated rats were enzymatically digested to deoxyribonucleosides and analyzed by high-pressure liquid chromatography. Several chromatographically distinct nucleoside-bound adducts were observed in lung whereas in the liver only one adduct was apparent. The major adduct formed in the lung was chromatographically identical to the adduct formed in the liver and represented 42 and 7% of total DNA binding in lung and liver, respectively. The major adduct (II) appeared to result from further metabolism of BP phenols. The BP diolepoxide adducts were not detected in rat liver, and only a relatively small amount was observed in rat lung, 1.4% of total DNA binding. The lack of formation of substantial amounts of BP diol-expoxide adducts in rat lung is consistent with the apparent lack of induction of pulmonary tumors in rat by BP. The BP-DNA adduct profiles were similar at both dose levels. Comparisons between the observed in vivo BP-DNA adduct profiles and profiles in various in vitro model systems are made. Bile samples were collected from bile-cannulated animals following i.v. dose of BP. With a 1.0-µmol/kg dose of BP, 68% of the dose was excreted into bile in six hr, and of this amount 34 and 9% represented glucuronide and sulfate conjugates, respectively. The remaining biliary metabolites were probably glutathione conjugates. Glucuronide and sulfate conjugates of phenols, diols, quinones, and uncharacterized more polar metabolites (pre-9, 10) were detected in bile. The benzo( a )pyrene-3,6-dione, 6.5% of dose, and pre-9, 10, 9% of dose, were the major glucuronide metabolites. The pre-9, 10 metabolites are probably polyhydroxylated BP derivatives recycled through the monooxygenase enzymes. Adduct II is probably formed from the interaction of DNA with reactive intermediates generated in the formation of pre-9, 10 metabolites.