期刊
LIVER INTERNATIONAL
卷 23, 期 6, 页码 405-409出版社
WILEY
DOI: 10.1111/j.1478-3231.2003.00869.x
关键词
aflatoxin B-1 biomarkers; cytochrome P450s; epoxide hydrolase; glutathione-S-transferase; p53 tumour suppressor gene; transgenic mice; woodchuck hepatitis virus
Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B-1 (AFB(1)), two of the major risk factors in the multifactorial aetiology of hepatocellular carcinoma (HCC), co-exist in those countries with the highest incidences of and the youngest patients with this tumour, raising the possibility of a synergistic carcinogenic interaction between the two agents. Experimental studies in HBV-transgenic mice and woodchucks infected with woodchuck hepatitis virus were the first to show a synergistic hepatocarcinogenic effect between hepadnaviral infection and AFB(1) exposure. With the availability of urinary and serum biomarkers that more accurately reflect dietary exposure to AFB(1) than did the initially used food sampling and dietary questionnaires, cohort studies of patients with HCC in China and Taiwan have provided compelling evidence for a multiplicative or sub-multiplicative interaction between HBV and AFB(1) in the genesis of human HCC. A number of possible mechanisms for the interaction have been suggested. Chronic HBV infection may induce the cytochrome P450s that metabolise inactive AFB(1) to the mutagenic AFB(1)-8,9-epoxide. Hepatocyte necrosis and regeneration and the generation of oxygen and nitrogen reactive species resulting from chronic HBV infection increase the likelihood of the AFB(1)-induced p53 249(ser) and other mutations and the subsequent clonal expansion of cells containing these mutations. Nuclear excision repair, which is normally responsible for removing AFB(1)-DNA adducts, is inhibited by HBVxprotein, favouring the persistence of existing mutations. This protein also increases the overall frequency of DNA mutations, including the p53 249(ser) mutation, and may contribute to uncontrolled cell cycling when p53 is non-functional.
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