Kwei G Y, Zaleski J, Irwin S E, Thurman R G, Kauffman F C
Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey 08854.
Cancer Res. 1992 Mar 15;52(6):1639-42.
Benzo(a)pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), accepted as the ultimate carcinogen of benzo(a)pyrene, has a very short half-life in aqueous solutions yet induces lung tumors when injected into infant mice. To evaluate the possibility that metabolites of BPDE, principally in the form of stable conjugates, contribute to binding to DNA in peripheral tissues, infant mice were injected i.p. with 39 nmol (+/- ) anti-BPDE. One h after injection, 5% of the dose was recovered in serum and appeared mostly as conjugated metabolites (54% as glucuronides and 16% as glutathione conjugates). Amounts of direct acting electrophiles in serum estimated by trapping with DNA comprised less than 0.02% of the injected dose. No more than 10% of the radioactivity in extracts of liver, lung, and kidney was recovered as BPDE. Glutathione conjugates predominated in the liver and lung, whereas glucuronides were the major metabolites in kidney. Radioactivity bound to DNA in liver, lung, and kidney was 21.5, 42.7, and 7.8 pmol/mg, respectively. Despite the rapid conversion of BPDE to stable conjugates, 32P-postlabeling profiles of DNA adducts in lung closely resembled that noted after addition of BPDE directly to lung homogenate. Thus, the reactive intermediate as well as stable conjugates of BPDE may be transported to target tissues where they initiate tumors.
苯并(a)芘7,8 - 二氢二醇 - 9,10 - 环氧化物（BPDE）被公认为苯并(a)芘的最终致癌物，它在水溶液中的半衰期极短，但注射到幼鼠体内时会诱发肺部肿瘤。为了评估BPDE的代谢产物（主要以稳定结合物的形式）在外周组织中与DNA结合的可能性，给幼鼠腹腔注射39 nmol（±）反式 - BPDE。注射后1小时，5%的剂量在血清中被检测到，且大多以结合代谢产物的形式存在（54%为葡萄糖醛酸结合物，16%为谷胱甘肽结合物）。通过与DNA捕获法估算的血清中直接作用亲电试剂的量不到注射剂量的0.02%。肝脏、肺和肾脏提取物中的放射性中，回收得到的BPDE不超过10%。谷胱甘肽结合物在肝脏和肺中占主导，而葡萄糖醛酸结合物是肾脏中的主要代谢产物。肝脏、肺和肾脏中与DNA结合的放射性分别为21.5、42.7和7.8 pmol/mg。尽管BPDE迅速转化为稳定的结合物，但肺中DNA加合物的32P后标记图谱与直接向肺匀浆中添加BPDE后观察到的图谱非常相似。因此，BPDE的反应性中间体以及稳定结合物可能被转运到靶组织并在那里引发肿瘤。
