Said Mahmoud M, Ogawa Kumiko, Pitchakarn Pornsiri, Takahashi Satoru, Asamoto Makoto, Shirai Tomoyuki
J Toxicol Pathol. 2009 Dec;22(4):263-71. doi: 10.1293/tox.22.263. Epub 2009 Dec 21.
The present study was undertaken to investigate the effect of dietary supplementation with nimesulide or eugenol on N-nitrosodiethylamine (DEN)-initiated early hepatocarcinogenesis in F344 male rats. Both compounds did not alter the expression of cytochrome P450 (CYP) 2E1, the enzyme that plays a major role in the activation of DEN to genotoxic products; however, nimesulide induced the expression of CYP1A1. Western blot analysis revealed that COX-1 and COX-2 protein expressions were not modulated by DEN compared with normal controls. Furthermore, post-initiation feeding with nimesulide or eugenol did not modulate COX-2 protein expression in normal or DEN-treated rats, whereas eugenol significantly increased the liver prostaglandin E(2) (PGE(2)) levels of DEN-injected animals compared with the DEN controls. Ultimately, nimesulide or eugenol did not modify DEN-induced hepatocarcinogenesis as evidenced by insignificant changes in the number and size of preneoplastic placental glutathione S-transferase (GST-P) positive liver foci compared with the DEN controls. These results suggest that COX-2, as well as prostaglandin E(2), may play no role in the post-initiation development of DEN-induced rat hepatocarcinogenesis at an early stage.
本研究旨在探讨饮食中补充尼美舒利或丁香酚对F344雄性大鼠经N-亚硝基二乙胺（DEN）启动的早期肝癌发生的影响。两种化合物均未改变细胞色素P450（CYP）2E1的表达，该酶在将DEN激活为遗传毒性产物的过程中起主要作用；然而，尼美舒利诱导了CYP1A1的表达。蛋白质印迹分析显示，与正常对照组相比，DEN未调节COX-1和COX-2蛋白的表达。此外，在启动后用尼美舒利或丁香酚喂养，未调节正常或DEN处理大鼠的COX-2蛋白表达，而与DEN对照组相比，丁香酚显著提高了注射DEN动物的肝脏前列腺素E2（PGE2）水平。最终，与DEN对照组相比，尼美舒利或丁香酚未改变DEN诱导的肝癌发生，这表现为癌前胎盘谷胱甘肽S-转移酶（GST-P）阳性肝灶的数量和大小变化不显著。这些结果表明，COX-2以及前列腺素E2可能在DEN诱导的大鼠肝癌发生早期启动后的发展中不起作用。
