Nordenskjöld M, Svensson S A, Jernström B, Moldéus P, Dock L, Söderhäll S
Carcinogenesis. 1981;2(11):1151-60. doi: 10.1093/carcin/2.11.1151.
The release and reabsorption of benzo[a]pyrene (BP) metabolites were studied in isolated rat hepatocytes incubated with BP. There was a rapid uptake of BP by the hepatocytes which was followed by an excretion of organic as well as water-soluble metabolites. Upon further incubation the BP-dihydrodiols and BP-phenols were reabsorbed by the cells and finally excreted as water-soluble conjugates. The metabolism of BP by the hepatocytes also resulted in the formation and release of reactive intermediates to the incubation medium. The DNA-binding intermediates released from the cells were consistent with trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene-9,10-oxide(s) and 9-hydroxybenzo[1]pyrene-4,5-oxide(s). The BP-metabolites were found to bind to hepatocyte and fibroblast DNA. The degree of DNA binding was estimated as the formation of DNA strand breaks. BP metabolites formed within the hepatocytes and transferred to the fibroblasts were found to induce DNA strand breaks in the latter cells. Addition of DNA to the medium markedly decreased the fraction of single stranded DNA in these cells. Under conditions where the excretion from hepatocytes of BP-phenols and BP-dihydrodiols were increased, the amount of DNA strand breaks in the fibroblasts increased.
在与苯并[a]芘（BP）一起孵育的离体大鼠肝细胞中，研究了BP代谢物的释放和重吸收。肝细胞对BP有快速摄取，随后排出有机和水溶性代谢物。进一步孵育后，BP - 二氢二醇和BP - 酚被细胞重吸收，最终以水溶性缀合物的形式排出。肝细胞对BP的代谢还导致反应性中间体形成并释放到孵育培养基中。从细胞中释放的与DNA结合的中间体与反式 - 7,8 - 二羟基 - 7,8 - 二氢苯并[a]芘 - 9,10 - 氧化物和9 - 羟基苯并[1]芘 - 4,5 - 氧化物一致。发现BP代谢物与肝细胞和成纤维细胞的DNA结合。DNA结合程度通过DNA链断裂的形成来估计。在肝细胞内形成并转移到成纤维细胞的BP代谢物被发现会诱导后者细胞中的DNA链断裂。向培养基中添加DNA显著降低了这些细胞中单链DNA的比例。在肝细胞中BP - 酚和BP - 二氢二醇排泄增加的条件下，成纤维细胞中DNA链断裂的数量增加。
