Nakae D, Mizumoto Y, Yoshiji H, Andoh N, Horiguchi K, Shiraiwa K, Kobayashi E, Endoh T, Shimoji N, Tamura K
Department of Oncological Pathology, Nara Medical University.
Jpn J Cancer Res. 1994 May;85(5):499-505. doi: 10.1111/j.1349-7006.1994.tb02386.x.
The present study was performed to assess the roles of hepatocellular oxidative damage to DNA and constituents other than DNA in rat liver carcinogenesis caused by a choline-deficient, L-amino acid-defined (CDAA) diet by examining the effects of the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD). The parameters used for cellular oxidative damage were the level of 8-hydroxy-guanine (8-OHGua) for DNA and that of 2-thiobarbituric acid-reacting substance (TBARS) for constituents other than DNA. A total of 40 male Fischer 344 rats, 6 weeks old, were fed the CDAA diet for 12 weeks with or without DPPD (0.05, 0.10 or 0.20%) or butylated hydroxytoluene (BHT, 0.25%). In the livers of the rats, the numbers and sizes of glutathione S-transferase (EC 2.5.1.18) placental form (GSTP)- and/or gamma-glutamyltransferase (GGT, EC 2.3.2.2)-positive lesions and levels of 8-OHGua and TBARS were determined. The GSTP-positive lesions of 0.08 mm2 or larger were all stained positively for GGT as well in cross-sectional area, whereas the smaller lesions were generally negative for GGT. DPPD and BHT reduced the size of the GSTP-positive lesions without affecting their total numbers. At the same time, they reduced TBARS generation without affecting 8-OHGua formation in DNA. The present results indicate that oxidative DNA damage (represented by 8-OHGua formation) and damage to constituents other than DNA (represented by TBARS generation) may play different roles in rat liver carcinogenesis caused by the CDAA diet; the former appears to be involved in the induction of phenotypically altered hepatocyte populations while the latter may be related to the growth of such populations.
本研究旨在通过检测抗氧化剂N，N'-二苯基对苯二胺（DPPD的作用，评估胆碱缺乏、L-氨基酸限定（CDAA）饮食诱导大鼠肝癌过程中，肝细胞DNA及非DNA成分的氧化损伤所起的作用。用于评估细胞氧化损伤的参数包括，DNA的8-羟基鸟嘌呤（8-OHGua）水平以及非DNA成分的硫代巴比妥酸反应物质（TBARS）水平。选取40只6周龄雄性Fischer 344大鼠，分为4组，分别喂食含或不含DPPD（0.05%、0.10%或0.20%）或丁基化羟基甲苯（BHT，0.25%）的CDAA饮食12周。测定大鼠肝脏中谷胱甘肽S-转移酶（EC 2.5.1.18）胎盘型（GSTP）和/或γ-谷氨酰转移酶（GGT，EC 2.3.2.2）阳性病变的数量和大小，以及8-OHGua和TBARS水平。面积≥0.08mm2的GSTP阳性病变在横截面积上GGT染色也均为阳性，而较小的病变GGT通常为阴性。DPPD和BHT可减小GSTP阳性病变的大小，但不影响其总数。同时，二者可减少TBARS生成，但不影响DNA中8-OHGua的形成。本研究结果表明，氧化DNA损伤（以8-OHGua形成为代表）和非DNA成分损伤（以TBARS生成为代表）在CDAA饮食诱导大鼠肝癌过程中可能发挥不同作用；前者似乎参与了表型改变的肝细胞群体的诱导，而后者可能与这些群体的生长有关。
