肝癌病人80%以上伴有肝硬化，肝硬化病人有约10%发展成肝癌。尽管亚硝胺类作为前致癌物引发肝癌已有动物实验和人体流行病学依据，但尚未确定其致癌性与CYP2E1代谢亚硝胺类活性的相关性。根据我们前期发现的肝癌病人肝硬化肝CYP2E1代谢活性明显升高，提出“CYP2E1活性增高，代谢亚硝胺类前致癌物增多，而引发肝癌”的假说。.以前期收集的150例正常人肝和120例肝癌病人肝硬化肝为研究对象，研究CYP2E1代谢氯唑沙宗、二甲基亚硝胺和二乙基亚硝胺的酶动力学改变及机制，并确定其相关性；以正常大鼠、基因敲除大鼠及酶抑制大鼠为研究对象，研究CYP2E1代谢亚硝胺类活性与致癌性之间的相关性，以确定CYP2E1的活性变化与肝癌发生的因果关系；以正常人、单纯性肝硬化病人、肝硬化肝癌病人为研究对象，研究氯唑沙宗的药动学，以确定肝癌病人体内CYP2E1的变化。这可为肝癌病人的早防早治提供新的作用靶点。

Approximately 10% cirrhotic patients can develop into hepatocellular carcinoma (HCC), and more than 80% HCC patients are accompanied by cirrhosis. Although it has been reported that nitrosamines can act as procarcinoges inducing hepatocarcinogenesis, which was supported by animal experiment and human epidemiology study, the correlation of their carcinogenicity and metabolic activity of CYP2E1 has not been determined. Based on the significantly increased CYP2E1 activity in cirrhotic livers of HCC patients in our early studies, we hypothesize that increased CYP2E1 activity may produce enhanced metabolism of nitrosamines to carcinogens, thus leading to HCC.. We have already built up of a bank including 150 normal human livers and 120 cirrhotic livers from HCC patients. The alteration in enzyme kinetics of chlorzoxazone, dimethylnitrosamine and diethylnitrosamine metabolized by CYP2E1, the correlation of their metabolic activity CLint, the relationship between the alteration in CYP2E1 activity and protein content as well as gene polymorphisms would been determined in 150 normal livers and 120 cirrohotic livers from HCC patients. The correlation between metabolic activity of nitrosamines by CYP2E1 and their carcinogenicity will be investigated in wild-type, cyp2e1 gene knock-out and CYP2E1 inhibitor-treated rats to ascertain that increased or decreased CYP2E1 activity can induce or inhibit nitrosamines-promoted hepatocarcinogenesis. The pharmacokinetics of chlorzoxazone will be examined in healthy volunteers, simple liver cirrhotic patients, and HCC patients with cirrhosis to determine changes of CYP2E1 activity in HCC patients. If this hypothesis could be verified, it would provide a new target for early prevention and treatment of HCC.