Aflatoxin B1-induced hepatocellular carcinoma in developing countries: Geographical distribution, mechanism of action and prevention

Abstract

Hepatocellular carcinoma (HCC) is the most well-known primary liver malignancy worldwide. Its incidence is rising at alarming rates and has become a public concern globally. It is more frequent in developing countries than in industrialized countries with respect to geographical variation, ethnic disparities and socioeconomic status. Dietary exposure to aflatoxins is among the major HCC risk factors. Aflatoxin B1, which is a genotoxic hepatocarcinogen, which presumptively causes cancer by inducing DNA adducts leading to genetic changes in target liver cells. AFB1 is metabolized by cytochrome-P450 enzymes to the reactive intermediate AFB1-8, 9 epoxide (AFBO) which binds to liver cell DNA, resulting in DNA adducts. DNA adducts interact with the guanine bases of liver cell DNA and cause a mutational effect in the P53 tumor suppressor gene at the codon 249 hotspot in exon 7, which may lead to HCC. Approximately 4.5 billion of the world's population is exposed to aflatoxin-contaminated food, particularly in low-income countries. Prevention involves treating crops that are susceptible to fungal contamination, appropriate handling of foodstuffs and the use of chemopreventive intervention. Moreover, an integrated network collaboration of different sectors, including public health, agricultural departments and mass media, is required to ensure effective food regulation systems so as to minimize the contamination of food by aflatoxins.

Keywords: DNA adducts; aflatoxin B1; chemopreventive agents; dietary changes; hepatocellular carcinoma; interventions.

Figure 1

Structure of AFB1 (27).

Figure 2

Biotransformation of AFB1, which comprises CYP450-mediated reactions resulting in a highly nucleophilic genotoxic reactive intermediate (AFBO), hydroxylation (to AFM1 and AFQ1) or demethylation (to AFP1). When AFBO binds to liver cell DNA, it causes mutation of p53 that may lead to HCC. AFBO is also capable of causing aflatoxicosis when it binds to protein amino acids. AFB1, aflatoxin B1; AFBO, AFB1-8, 9 epoxide.

Figure 3

Detoxification pathway of the AFBO intermediate. AFB1, aflatoxin B1; AFBO, AFB1-8, 9 epoxide; GST, glutathionine S-transferase.

Figure 4

Proposed scheme for aflatoxin prevention.