Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis.
Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1), 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 AFB1 exposure. With the availability of urinary and serum biomarkers that more accurately reflect dietary exposure to AFB1 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 AFB1 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 AFB1 to the mutagenic AFB1-8,9-epoxide. Hepatocyte necrosis and regeneration and the generation of oxygen and nitrogen reactive species resulting from chronic HBV infection increase the likelihood of the AFB1-induced p53 249ser and other mutations and the subsequent clonal expansion of cells containing these mutations. Nuclear excision repair, which is normally responsible for removing AFB1-DNA adducts, is inhibited by HBV x protein, favouring the persistence of existing mutations. This protein also increases the overall frequency of DNA mutations, including the p53 249ser mutation, and may contribute to uncontrolled cell cycling when p53 is non-functional.
Kew
Michael C
MC
MRC/CANSA/University Molecular Hepatology Research Unit, Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. kewmc@medicine.wits.ac.za
D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000503:physiopathology; D003043:Cocarcinogenesis; D005506:Food Contamination; D005658:Fungi; D006515:Hepatitis B virus / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000503:physiopathology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000503:physiopathology
D016604:Aflatoxin B1