Kirby G M, Chemin I, Montesano R, Chisari F V, Lang M A, Wild C P
International Agency for Research on Cancer, Lyon, France.
Mol Carcinog. 1994 Oct;11(2):74-80. doi: 10.1002/mc.2940110204.
The relative roles of hepatitis B virus (HBV) and aflatoxin and their possible mechanism of interaction in the etiopathogenesis of hepatocellular carcinoma (HCC) are not understood. One hypothesis is that viral infection and associated liver injury alter expression of carcinogen-metabolizing enzymes. We tested this hypothesis in an HBV-transgenic mouse model in which a synergistic interaction occurs between aflatoxin B1 (AFB1) and HBV in the induction of HCC (Sell et al., Cancer Res 51:1278-1285, 1991). In this transgenic mouse lineage, overproduction of the HBV large envelope protein results in progressive liver cell injury, inflammation, and regenerative hyperplasia. Initially, two cytochrome P450s of importance in AFB1 metabolism in the mice were identified, namely Cyp2a-5 and Cyp3a, using specific antibodies and chemical inhibitors. The expression of these P450 isoenzymes and an alpha-class glutathione S-transferase (GST) isoenzyme, YaYa, were examined. Increased expression and altered distribution of Cyp2a-5 were demonstrated, by immunohistochemical analysis, to be associated with the development of liver injury in mice and to increase with age between 1 and 12 months. Cyp3a expression was also increased in HBV-transgenic mice, but the increase was not as clearly related to age. GST YaYa levels were the same in HBV-transgenic mice and their nontransgenic littermates of all ages. These results show that expression of specific cytochrome P450s is altered in association with overexpression of HBV large envelope protein and liver injury in this model. This may have general relevance to human HCC, the etiology of which is associated with a diverse range of liver-damaging agents.
乙型肝炎病毒（HBV）和黄曲霉毒素在肝细胞癌（HCC）发病机制中的相对作用及其可能的相互作用机制尚不清楚。一种假说是病毒感染及相关的肝损伤会改变致癌物代谢酶的表达。我们在一个HBV转基因小鼠模型中验证了这一假说，在该模型中黄曲霉毒素B1（AFB1）和HBV在诱发HCC方面存在协同相互作用（Sell等人，《癌症研究》51:1278 - 1285，1991）。在这个转基因小鼠品系中，HBV大包膜蛋白的过量产生导致进行性肝细胞损伤、炎症和再生性增生。最初，使用特异性抗体和化学抑制剂，在小鼠体内鉴定出了两种对AFB1代谢重要的细胞色素P450，即Cyp2a - 5和Cyp3a。检测了这些P450同工酶和一种α类谷胱甘肽S - 转移酶（GST）同工酶YaYa的表达。免疫组织化学分析表明，Cyp2a - 5表达增加和分布改变与小鼠肝损伤的发展相关，并且在1至12个月龄之间随年龄增长而增加。Cyp3a在HBV转基因小鼠中的表达也增加，但这种增加与年龄的关系不那么明显。各年龄段的HBV转基因小鼠及其非转基因同窝小鼠的GST YaYa水平相同。这些结果表明，在该模型中特定细胞色素P450的表达改变与HBV大包膜蛋白的过表达及肝损伤相关。这可能与人类HCC具有普遍相关性，人类HCC的病因与多种肝损伤因素有关。
