Study on the mechanism of the chemical carcinogenesis of cirrhotic liver

本文研究了还原型谷胱甘肽（GSH）和乙醇对黄曲霉毒素B_1（AFB_1）诱导的原代培养肝细胞DNA单链断裂和AFB_1-DNA加合物形成的影响。丁硫酰磺酰亚胺（BSO）使细胞内GSH下降至对照组的13%，使AFB_1处理的肝细胞DNA断裂增加至对照组的17%以上。因此，肝细胞GSH水平的降低增加了AFB_1诱导的DNA损伤。虽然乙醇本身不会引起DNA损伤，但BSO和乙醇的组合使BSO单独使用的百分比增加了23%以上。BSO可显著促进[^3H]AFB_1-DNA加合物的形成，乙醇可进一步促进[^3H]AFB_1-DNA加合物的形成，而乙醇对GSH、总细胞色素P-450、谷胱甘肽S-转移酶和环氧化物水解酶的含量无影响。然而，GSH耗竭大鼠肝细胞暴露于乙醇显着增加细胞色素P450 IIIA的水平，激活AFB_1。乙醇在BSO存在下的增强作用可能是由于这种酶在大鼠肝细胞中的诱导。

The effects of reduced glutathione (GSH) and ethanol on aflatoxin B_1 AFB_1)-induced DNA single strand breaks and AFB_1-DNA adduct formation were studied in primary cultured hepatocytes. Buthionine sulphoximine (BSO) decreased intracellular GSH to 13% of those of control levels, increased DNA fragmentation of AFB_1-treated hepatocytes by over 17% of those without BSO. Thus a decrease in hepatocyte GSH levels increased AFB_1-induced DNA damage. Although ethanol in itself did not induce DNA damage, a combination of BSO and ethanol increased the percentage by over 23% of that with BSO only. BSO significantly enhanced the formation of [^3H]AFB_1-DNA adducts and ethanol further increased it in the presence of BSO, whereas ethanol did not affect the amount of GSH, total cytochrome P-450, glutathione S-transferase and epoxide hydrolase in cultured hepatocytes. However, GSH-depleted rat hepatocytes exposed to ethanol significantly increased the level of cytochrome P450IIIA, which activates AFB_1. The enhancing effects of ethanol in the presence of BSO are probably due to the induction of this enzyme in rat hepatocytes.